ES2312917T3 - PHARMACEUTICAL COMPOSITIONS THAT INCLUDE TAQUIQUININE ANTAGONISTS AND AN INHIBITOR OF SEROTONIN RECAPTATION. - Google Patents

Abstract

A composition comprising a compound of formula (I) (See formula) in which R represents a halogen atom or a C1-4 alkyl group; R1 represents hydrogen or a C1-4 alkyl group; R 2 represents hydrogen, a C 1-4 alkyl group, or a C 2-6 alkenyl or C 3-7 cycloalkyl group; or R1 and R2 together with the nitrogen and carbon atom to which they are attached respectively represent a 5- to 6-membered heterocyclic group; R3 represents a trifluoromethyl group, a C1-4 alkyl, a C1-4 alkoxy, a trifluoromethoxy or a halogen; R4 represents hydrogen, a group (CH2) qR7 or (CH2) rCO (CH2) pR7; R5 represents hydrogen or a C1-4 alkyl group or a COR6; R7 represents hydrogen, hydroxy or NR8R9 in which R8 and R9 independently represent hydrogen or C1-4 alkyl optionally substituted by hydroxy or by amino; R10 represents hydrogen, a C1-4 alkyl group or R10 together with R2 represents a C3-7 cycloalkyl group; m is zero or an integer from 1 to 3; n is zero or an integer of 1 of 3; both p and r are independently zero or an integer from 1 to 4; q is an integer from 1 to 4; provided that, when R1 and R2 together with the nitrogen and carbon atom to which they are attached respectively represent a 5- to 6-membered heterocyclic group, i) m is 1 or 2; ii) when m is 1, R is not fluorine and iii) when m is 2, the two substituents R are neither fluorine, or their pharmaceutically acceptable salts or solvates and a selective serotonin reuptake inhibitor.

Description

Pharmaceutical compositions comprising tachykinin antagonists and a reuptake inhibitor of the serotonin racaptation.

The present invention relates to a composition comprising piperazine derivatives and a selective inhibitor of serotonin reuptake, to procedures for its preparation, to pharmaceutical compositions containing them and their use doctor.

In particular, the invention relates to a composition comprising new compounds that are potent and specific tachykinin antagonist agents, including substance P and other neurocinins and a selective inhibitor of serotonin reuptake.

U.S. Patent Document No. 4308387 describe some diphenyl-butyl-piperazine-carboxamides  that have the following formula (A)

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one

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in which R_ {1}, R2_, R 3, R 4, R 5 and R 6 can be selected from hydrogen, alkyl, cycloalkyl, aralkyl, alkenyl and phenyl; X is O or S. Such compounds are useful in the treatment of disorders Mental

The patent application document International WO 97/36593 describes certain compounds that inhibit farnesyl protein transferase, that they have, when it is realized that G = H_ {2}, R_ {4} = H, s = O, X = CO, p = 0, n = 0, A_ {1} = A_ {2} = one link, the following structure (B),

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2

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in the that

Z can be, among other things, alkyl optionally substituted with hydroxy or NR 6 R 7;

W can be, among other things, a radical heterocyclic,

R2 can be, among other things, hydrogen, methyl, alkyl, -CONR 6 R 7 or -COOR 6;

Aryl_ {1} may be, among other things, optionally substituted with fluorine;

R_ {9} can be, among other things, hydrogen or alkyl;

R_ {8} can be, among other things, hydrogen, (per) fluoroalkyl, alkyl, alkoxy, F, Cl, Br.

However, in the aforementioned documents no There is no disclosure or any suggestion about anyone of the compounds claimed herein.

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The present invention provides a Composition comprising compounds of formula (I):

3

at that

R represents a halogen atom or a group C 1-4 alkyl;

R1 represents hydrogen or an alkyl group C 1-4;

R2 represents hydrogen or an alkyl group C 1-4;

R 3 represents a trifluoromethyl group, a C 1-4 alkyl, an alkoxy C 1-4, a trifluoromethoxy or a halogen;

R 4 represents hydrogen, a group (CH2) qR7 {or (CH 2) rCO (CH 2) pR 7;

R 5 represents hydrogen or an alkyl C 1-4;

R 7 represents hydrogen, hydroxy, or NR_ {8} R_ {9} in which R_ {8} and R_ {9} represent independently hydrogen or C 1-4 alkyl optionally substituted by hydroxy or by amino;

R 10 represents hydrogen;

m is zero or an integer from 1 to 3; n is zero or an integer from 1 to 3; both p and r are independently zero or an integer from 1 to 4; q is an integer from 1 to 4;

and its salts and solvates pharmaceutically acceptable and a selective reuptake inhibitor of serotonin

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A further embodiment of the invention provides a composition comprising compounds of formula (I) and their salts and pharmaceutically acceptable solvates, in which

R represents a halogen atom or a group C 1-4 alkyl;

R1 represents hydrogen or an alkyl group C 1-4;

R2 represents hydrogen, an alkyl group C 1-4, C 2-6 alkenyl or C 3-7 cycloalkyl; or R1 and R2 together with the nitrogen and carbon atom to which they are attached respectively they represent a heterocyclic group of 5 to 6 members;

R 3 represents a trifluoromethyl group, a C 1-4 alkyl, an alkoxy C 1-4, a trifluoromethoxy or a halogen;

R 4 represents hydrogen, a group (CH2) qR7 {or (CH 2) rCO (CH 2) pR 7;

R 5 represents hydrogen or an alkyl C 1-4;

R 7 represents hydrogen, hydroxy or NR_ {8} R_ {9} in which R_ {8} and R_ {9} represent independently hydrogen or C 1-4 alkyl optionally substituted by hydroxy or by amino;

R 10 represents hydrogen, an alkyl group C_ {1-4} or

R_ {10} together with R2 represents a group C 3-7 cycloalkyl;

m is zero or an integer from 1 to 3; n is zero or an integer of 1 of 3; both p and r are independently zero or an integer from 1 to 4; q is an integer from 1 to 4; to condition that when R_ {1} and R2 together with the atom of nitrogen and carbon to which they are attached respectively represent a 5- to 6-membered heterocyclic group, i) m being 1 or 2; ii) when m is 1, R is not fluorine and iii) when m is 2, the two R substituents are not fluorine and a selective inhibitor of Serotonin reuptake.

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Appropriate pharmaceutically acceptable salts of the compounds of general formula (I) include salts by addition of acids, which have been formed with organic acids or inorganic pharmaceutically acceptable, for example hydrochlorides, hydrobromides, sulfates, alkyl- or aryl sulphonates (e.g. methane sulphonates or p-toluene sulphonates), phosphates, acetates, citrates, succinates, tartrates, smokers and maleates.

Solvates can be, for example, hydrates

References made hereafter to a compound according to formula (I) include both compounds of formula (I) as well as its salts by the addition of acids pharmaceutically acceptable, together with solvates pharmaceutically acceptable.

Those skilled in the art will appreciate that in the technique the compounds of formula (I) contain at least one center chiral (that is, the carbon atom shown with the * symbol in the formula (I)). Other asymmetric carbon atoms are possible in the compounds of formula (I). That's why, for example, when R2 is a C1-4 alkyl group, a C 2-6 alkenyl or C cycloalkyl 3-7, and R 5 and R 10 are hydrogens, the compounds of formula (I) possess two asymmetric carbon atoms and these can be represented by the formulas (1a, 1b, 1c and 1d).

4

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5

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The wedge-shaped link indicates that the link It is above the plane of the paper. The broken link indicates that the link is below the plane of the paper.

The configuration shown for the atom of chiral carbon, indicated as * in formulas 1b and 1d, is quoted as then as the β configuration, and the one shown in the formulas 1a and 1c are cited as the α configuration.

In general, in specific compounds mentioned below, the β configuration next to the atom of chiral carbon indicated as * corresponds to the S isomer and the α configuration corresponds to the R isomer.

The configuration of the two carbon atoms chiral shown in formulas 1a and 1b are cited hereafter as the anti configuration, and the one shown in formulas 1c and 1d are cite as the configuration without.

In addition, when R2 is an alkyl group C 1-4, a C 2-6 alkenyl or a C 3-7 cycloalkyl or R 10 is a group C 1-4 alkyl and R 5 is an alkyl group C 1-4, the compounds of formula (I) possess three asymmetric carbon atoms.

The assignment of the R and S configurations of the asymmetric carbon atoms of the compounds of formula (I) it has been done according to the rules of Chan, Ingold and Prelong 1956, 12, 81.

It is to be understood that all enantiomers and diastereoisomers and all mixtures thereof are encompassed within of the scope of the formula (I).

The term "alkyl" is used herein as a group or a part of the group and refers to an alkyl group of linear or branched chain containing 1 to 4 carbon atoms; Examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

The term halogen refers to an atom of fluoride, chloride, bromide or iodide.

The term C 2-6 alkenyl defines straight or branched chain hydrocarbon radicals that they contain a double bond and they are 2-6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl or 3-hexenyl

The expression cycloalkyl group C 3-7 means a hydrocarbon ring non-aromatic monocyclic of 3 to 7 carbon atoms such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl

The expression alkoxy group C 1-4 may be a straight chain alkoxy group or branched, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy.

When R1 and R2 together with the atom of nitrogen and carbon to which they are attached respectively represent a 5- to 6-membered heterocyclic group this group is saturated or It contains a single double bond. This can be a group. 3,6-dihydro-2H-pyridin-1-yl, a piperidin-1-yl or a pyrrolidin-1-yl.

The group R 5 may be in position 3, 5 or 6 of the piperazine ring of the compounds of formula (I)

6

When R represents halogen this is suitably chloride or, more preferably, fluoride, or when R is C 1-4 alkyl this is suitably methyl or ethyl, in which m is 0 or an integer from 1 to 2.

Suitable values for R1 include hydrogen, a methyl, ethyl or propyl group.

Suitable values for R2 include hydrogen, a methyl group, ethyl, propyl, isopropyl, a group 2-propenyl or cyclopropyl.

Suitable values for R 3 include a methyl, ethyl or trifluoromethyl group.

When R 4 is (CH 2) qR 7 or (CH2) rCO (CH2) pR7, R7 is suitably hydrogen, hydroxy, NR 9 R 8, for example NH 2, NH (C 1-4 alkyl) for example Methyl NH or N (C 1-4 alkyl) 2  for example N (methyl) 2, NH (alkyl C 1-4) NH 2 for example NH (ethyl) NH2, NH (alkyl C_ {1-4}) in which q is 1 or 2 and both p and r they are independently zero or an integer from 1 to 2.

Suitable values for R5 include hydrogen or a C 1-4 alkyl group (for example methyl).

R is preferably a halogen atom (by example fluoride or chloride) and / or an alkyl group C 1-4 (for example methyl) and m is preferably an integer from 1 to 2.

Suitable values for R 10 include hydrogen, a C 1-4 alkyl group (for example methyl) or together with R2 represents a cycloalkyl group C 3-7 (for example cyclopropyl).

R1 is preferably a hydrogen atom or a methyl group.

R2 is preferably an atom of hydrogen, a methyl group, isopropyl, 2-propenyl, or cyclopropyl or together with R1 is a group 3,6-dihydro-2H-pyridin-1-yl, piperidin-1-yl or pyrrolidin-1-yl.

R 3 is preferably a group trifluoromethyl.

R 4 is preferably an atom of hydrogen, an amino-alkyl group C 1-4 (for example aminoethyl), aminoacetyl or amino (alkyl C 1-4 -aminocarbonyl).

R 5 is preferably an atom of hydrogen, a methyl or ethyl group.

R 10 is preferably an atom of hydrogen, a methyl group or together with R2 is cyclopropyl.

A preferred group of compounds of formula (I) are those in which the carbon atom shown with * is in the β configuration.

A preferred class of compounds of formula (I) are those in which R is independently selected from of a halogen or methyl group, in which m is 1 or 2. More preferably, m is 2. Within this class those in which R It is in position 2 and 4 are particularly preferred.

The compounds of formula (I) in which R 3 it is a trifluoromethyl group and n is 2 represent a preferred class of compounds and, within this class, R 3 is preferably in position 3 and 5.

A more preferred class of compounds of formula (I) are those in which R 4 is hydrogen, a group (CH 2) rCO (CH 2) pR 7 or (CH 2) q R 7, in which R 7 represents an amine. Within this class, those in which both p and r are independently zero or 1, or q is 1 or 2, they are particularly preferred.

A particularly preferred group of compounds of formula (I) is one in which R is independently selected  from halogen or methyl, R 3 is trifluoromethyl in both position 3 as in 5, R1 is hydrogen or methyl, R2 is hydrogen, methyl, 2-propenyl, or a group cyclopropyl or together with R1 is a group 3,6-dihydro-2H-pyridin-1-yl, piperidin-1-yl or pyrrolidin-1-yl, R 10 represents hydrogen, a methyl or R 10 together with R 2 is a cyclopropyl group, R 4 is hydrogen, an aminoacetyl group or amino-ethyl and R 5 is hydrogen or a group methyl.

A particularly preferred group of compounds of formula (I) is one in which R is independently selected  from halogen or methyl, R 3 is trifluoromethyl in both position 3 as in 5, R1 is hydrogen or methyl, R2 is hydrogen, methyl, 2-propenyl or a group cyclopropyl or together with R1 is a group 3,6-dihydro-2H-pyridin-1yl, piperidin-1-yl or pyrrolidin 1-yl, R 10 represents hydrogen, a methyl or R 10 together with R 2 is a cyclopropyl group, R 4 is hydrogen, and R5 is hydrogen.

Another particularly preferred group of compounds of formula (I) is one in which R is selected independently from halogen or methyl and m is 2, R3 it is trifluoromethyl in both position 3 and 5, R1 and R 2 are independently hydrogen or methyl, R 4 is hydrogen and R5 is hydrogen.

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Preferred compounds according to the invention are:

(3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid;

(3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (2-Isopropyl-phenyl) -piperazin-1-carboxylic acid;

(3,5-bis-trifluoromethyl-benzyl) methyl amide of the acid 2- (4-Fluoro-3-methyl-phenyl) -piperazin-1-carboxylic acid;

(3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (2,4-Difluoro-phenyl) -piperazin-1-carboxylic acid;

[1- (3,5-bis-trifluoromethyl-phenyl) ethyl] -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid;

(3,4-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (4-fluoro-phenyl) -piperazin-1-carboxylic acid;

(3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2-phenyl-piperazin-1-carboxylic;

(3,5-Bistrifluoromethyl-benzyl) -methyl-amide of the acid 2- (2,4-dichloro-phenyl) -piperazin-1-carboxylic acid;

(3,5-Bistrifluoromethyl-benzyl) -methyl-amide of the acid 2- (3,4-dichloro-phenyl) -piperazin-1-carboxylic acid;

(3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -3-methyl-piperazin-1-carboxylic acid;

(3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (2-methyl-4-fluoro-phenyl) -6-methyl-piperazin-1-carboxylic acid;

[1- (3,5-bis-trifluoromethyl-phenyl) ethyl] -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid;

(3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 4- (2-amino-acetyl) -2- (S) - (4-fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid;

(3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (S) - (4-Fluoro-2-methyl-phenyl) -4- (piperidin-4-carbonyl) -piperazin-1-carboxylic acid;

(3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 4- (2-amino-ethyl) -2- (S) - (4-fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid;

[(1-3,5-bis-trifluoromethyl-phenyl) -cyclopropyl] -methyl-amide of the acid 2- (S) - (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid;

[2- (3,5-bis-trifluoromethyl-phenyl) -pyrrolidin-1-yl] - [2- (S) - (4-fluoro-2-methyl-phenyl) -piperazin-1-yl] -methanone;

[2- (3,5-bis-trifluoromethyl-phenyl) -3,6-dihydro-2H-pyridin-1-yl] - [2- (S) - (4-fluoro-2-methyl-phenyl) -piperazin -1-il] -meta-
ninth;

[2- (3,5-bis-trifluoromethyl-phenyl) -piperidin-1-yl] - [2- (S) - (4-fluoro-2-methyl-phenyl) -piperazin-1-yl] -methanone;

[1- (3,5-bis-trifluoromethyl-phenyl) -but-3-enyl] -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid;

[1- (3,5-bis-trifluoromethyl-phenyl) -2-methyl-propyl] -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid;

[(3,5-bis-trifluoromethyl-phenyl) -cyclopropyl-methyl] -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid;

and enantiomers, pharmaceutically salts acceptable (for example, hydrochloride, methanesulfonate, acetate) and His solvates.

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Particularly preferred compounds according with the invention they are:

hydrochloride (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (S) - (4-Fluoro-2-methyl-phenyl) -4- (piperidin-4-carbonyl) -piperazin-1 carboxylic acid;

[2- (3,5-bis-trifluoromethyl-phenyl) -3,6-dihydro-2 H -pyridin-1-yl] - [2- (S) - (4-fluoro-2-methyl-phenyl) hydrochloride ) -piperazin-1-yl] -methanone (enantiomer A);

hydrochloride (3,5-bis-trifluoromethyl-benzyl) -methyl- acid amide 4- (2-amino-acetyl) -2- (S) - (4-fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid;

methanesulfonate [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-amide of the acid 2- (S) - (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid;

acetate [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-amide of the acid 2- (S) - (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid;

and his solvates;

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The compounds of the formula (I) are tachykinin antagonistic agents, including substance P and other neurocinins, both in vitro and in vivo, and are therefore useful in the treatment of conditions mediated by tachykinins, including substance P and other neurocinins. .

The binding affinity to NK1 receptors has been determined in vitro by the ability of the compounds to displace [3H] - substance P (SP) from recombinant human NK1 receptors, expressed in cell membranes. Chinese hamster ovary (from Chinese Hamster Ovary = CHO).

CHO cell membranes were prepared using a modification of the method described by Dam T and Quirion R ( Peptides , 7 : 855-864, 1986). Therefore, binding to a ligand was performed in 0.4 ml of 50 mM HEPES, pH 7.4, containing 3 mM of MnCl2, 0.02% BSA (bovine serum albumin), 0.5 nM of [3 H] - substance P (30? 56 Ci / mmol, Amersham), a final membrane concentration of 25 µg protein / ml, and the test compounds. The incubation was carried out at room temperature for 40 min. Nonspecific binding was determined using an excess of substance P (1 µM) and this represents approximately 6% of the binding
total.

The compounds of the formula (I) were further characterized in a functional assay for the determination of their inhibitory effect. Human CHO-NK1 cells were stimulated with substance P and receptor activation was evaluated by measuring the accumulation of cytidinediphospho-diacylglycerol (CDP-DAG) which is the liponucleotide precursor of phosphatidyl inositol diphosphate. CDP-DAG accumulates in the presence of Li + as a result of receptor-mediated phospholipase C (PLC) activation (Godfrey, Biochem. J. , 258 : 621-624, 1989). The method is described in detail by Ferraguti et al. ( Mol. Cell. Neurosci ., 5 : 269-276, 1994).

The action of the compounds of formula (I) in the NK1 receptor can be determined using assays conventional. Therefore, the ability to attach to the receiver of NK_ {1} was determined using the paracentesis model of the leg of a gerbil, as described by Rupniak & Williams, Eur. J. of Pharmacol., 1994.

It has also been found that the compounds of formula (I) exhibit an anxiolytic activity in trials conventional. For example, in the human threat test to a tití (Costall et al., 1988).

The compounds of formula (I) may be useful in the treatment of central nervous system (CNS) disorders, in particular in the treatment or prevention of disorders major depressants, including a bipolar depression, a unipolar depression, single major depressive episodes or recurring with or without psychotic traits, catatonic traits, traits melancholic, atypical features or postpartum access, the Anxiety treatment and treatment of panic disorders. Other mood disorders, which are covered within the expression of major depressive disorders, include a dysthymic disorder with early or late access and with or without atypical features, neurotic depression, disorders of the stress after trauma, and social phobia; a dementia of type of Alzheimer's, with early or late access, with provision of depressed mood, vascular dementia with mood disposition depressed mood disorders, induced by alcohol, amphetamines, cocaine, hallucinogens, agents for inhalation, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and other substances; a schizoaffective disorder of depressed type; and a mood adjustment disorder depressed Major depressive disorders may result. also of a general medical condition that includes, but is not limited to, myocardial infarction, diabetes, heart attack (malogro) or abortion, etc.

The compounds of formula (I) are useful as analgesic agents In particular, they are useful in the treatment of a traumatic pain, such as a postoperative pain, a pain from traumatic avulsion such as that of the brachial plexus; a pain chronic such as arthritic pain as it appears in cases of a bone, rheumatoid or psoriatic arthritis; a neuropathic pain such as a post-herpetic neuralgia, a neuralgia trigeminal, a segmental or intercostal neuralgia, a fibromyalgia, a causalgia, a peripheral neuropathy, a diabetic neuropathy, a chemotherapy-induced neuropathy, an AIDS-related neuropathy, an occipital neuralgia, a geniculate neuralgia, a glossopharyngeal neuralgia, a dystrophy sympathetic reflex, an illusory pain of a body member; various forms of headache or migraine, such as migraine, acute or chronic tension headache, temporomandibular pain, maxillary sinus pain, clustered headache, odontalgia; pain caused by cancer; visceral pain, pain gastrointestinal; nerve pinching pain; pain for sports injuries; dysmenorrhea, menstrual pain; meningitis; arachnoiditis, musculoskeletal pain; lower back pain; eg spinal stenosis; prolapse disc; sciatica; angina; ankylosing spondylitis; gout; burns, pains of scarring, itching; and thalamic pain such as thalamic pain after a stroke.

The compounds of formula (I) are also useful in the treatment of sleep disorders including dysomnia, insomnia, sleep apnea, narcolepsy and rhythm disorders circadian.

The compounds of formula (I) are also useful in the treatment or prevention of cognitive disorders. The cognitive disorders include dementia, amnesic disorders and cognitive disorders, which have not been specified by another mode.

In addition, the compounds of formula (I) are useful also as agents that enhance memory and / or knowledge in healthy human beings, without any cognitive defect and / or memory.

The compounds of formula (I) are also useful in the treatment of a tolerance to a certain number of substances and a dependence on them. For example, they are useful in the treatment of a dependency regarding of nicotine, alcohol, caffeine, phencyclidine (compounds similar to phencyclidine), or in the treatment of tolerance to, and dependence on opiates (eg cannabine, heroin, morphine) or benzodiazepines; in the treatment of an addiction to cocaine, sedatives, hypnotics, amphetamines or related drugs with amphetamines (eg dextro-amphetamine, methyl amphetamine), or a combination of these.

The compounds of formula (I) are also useful as anti-inflammatory agents. In particular, they are useful in the treatment of an inflammation in asthma, influenza, chronic bronchitis and rheumatoid arthritis; in the treatment of inflammatory diseases of the gastrointestinal tract, such as Crohn's disease, ulcerative colitis, inflammatory disease of the intestines and drug-induced injury non-steroidal anti-inflammatories; diseases inflammatory skin such as herpes and eczema; diseases Bladder inflammations such as cystitis and incontinence urgent; and eye and dental inflammations.

The compounds of formula (I) are also useful in the treatment of allergic disorders, in particular disorders skin allergies such as hives, and allergic disorders of the airways such as rhinitis.

The compounds of formula (I) are also useful in the treatment of emesis, i.e. nausea, retching and vomiting Emesis includes acute emesis, delayed emesis and an anticipatory emesis. The compounds of formula (I) are useful in the treatment of emesis however induced. By For example, an emesis can be induced by drugs such as chemotherapeutic agents against cancer such as agents alkylating agents, eg cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, eg dactinomycin, doxorubicin, mitomycin-C and bleomycin; anti-metabolites, eg cytarabine, methotrexate and 5-fluoro-uracil; alkaloids of vinca, eg etoposide, vinblastine and vincristine; and others such as cisplatin, dacarbazine, procarbazine and hydroxyurea; Y combinations of them; ailments caused by radiation; therapy by radiation, eg irradiation of the chest or abdomen, such as in the treatment of cancer; poisons toxins such as toxins caused by metabolic disorders or an infection, eg gastritis, or released during an infection bacterial or viral gastrointestinal; a pregnancy; disorders vestibular, such as motion sickness, vertigo, vahido or fading, and Méniere's syndrome; ailments postoperative; gastrointestinal obstruction; mobility reduced gastrointestinal; visceral pain, eg heart attack myocardium or peritonitis; migraine; increased intercranial pressure; decreased intercranial pressure (eg altitude sickness); opioid analgesics, such as morphine; and reflux disease gastroesophageal; indigestion caused by acids, indulgence excessive food or drink, acid stomach, sour stomach, heartburn / regurgitation, cardialgias, such as episodic cardialgia, nocturnal cardialgia and food-induced cardialgia; Y dyspepsia.

The compounds of formula (I) are also useful in the treatment of gastrointestinal disorders such as irritable bowel syndrome, skin disorders such as psoriasis, pruritus and sunburn; vasospastic disorders such as angina, vascular headache and Reynaud's disease; cerebral ischemia such as cerebral vasospasm following a subarachnoid hemorrhage; fibrous diseases and by collagens such as scleroderma and eosinophilic fascioliasis; disorders related to the intensification or suppression of immunity such as systemic lupus erythematosus and diseases rheumatic such as fibrositis; And cough.

The compounds of formula (I) have a particular utility in the treatment of depressive states, in the Treatment of anxiety and panic disorders.

Depressive states include major depressive disorders, including bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic traits, catatonic traits, melancholic traits, atypical traits or access after delivery, a dysthymic disorder with access early or late and with or without atypical features, neurotic depression and social phobia; Alzheimer's type dementia, with early or late access, with depressed mood; vascular dementia with depressed mood; mood disorders, induced by alcohol, amphetamines, cocaine, hallucinogens, inhalation agents, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and other substances; a schizoaffective disorder of the type
depressed.

The compounds of formula (I) can be administer in combination with other active substances such as 5HT3 antagonist agents, serotonin agonist agents, selective serotonin reuptake inhibitors (SSRI, from selective serotonin reuptake inhibitors), agents norepinephrine reuptake inhibitors (SNRI, from noradrenaline re-uptake inhibitors), agents tricyclic antidepressants or antidepressant agents dopaminergic

Appropriate 5HT3 antagonist agents, which are they can use in combination with the compounds of formula (I), include, for example, ondansetron, granisetron and metoclopramide

Appropriate serotonin antagonist agents, which can be used in combination with the compounds of formula (I), include sumatriptan, rauwolscina, yohimbine and metoclopramide

Appropriate SSRIs, which can be used in combination with the compounds of formula (I), include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline and zimeldine.

Appropriate SNRIs, which can be used in combination with the compounds of formula (I), include venlafaxine and reboxetine.

Appropriate tricyclic antidepressant agents, which can be used in combination with a compound of formula (I), include imipramine, amitriptyline, clomipramine and nortriptyline

Appropriate antidepressant agents dopamine, which can be used in combination with a compound of formula (I) include bupropion and amineptin.

It will be appreciated that the compounds of the combination or composition can be administered simultaneously (already either in the same pharmaceutical formulation or in different pharmaceutical formulations) or consecutively.

Therefore, a composition is provided comprising a compound of formula (I) or a salt or a solvate pharmaceutically acceptable thereof and a selective inhibitor of serotonin reuptake for use in therapy, particularly in human medicine

It is also provided, as an aspect additionally, the use of a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate of this in the preparation of a medicine intended for use in the treatment of tachykinin-mediated conditions, including substance P and other neurocinins.

It will be appreciated that the reference to one treatment includes prophylaxis as well as relief of established symptoms

The compounds of formula (I) can be administer as the raw chemical, but the ingredient active is preferably presented as a formulation Pharmaceutical

Correspondingly, the invention provides also a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically salt thereof acceptable and a selective reuptake inhibitor of serotonin, and that has been formulated for administration by any convenient way. These compositions are found preferably in a form adapted for use in medicine, in particular in human medicine, and conveniently you can formulate in a conventional manner using one or more vehicles or pharmaceutically acceptable excipients.

Thus, the compounds of formula (I) can be formulate for administration orally, orally, parenterally, topical (including ophthalmic and nasal), deposit (release delayed) or rectal, or in a manner appropriate to the administration by inhalation or insufflation (either through the mouth or nose)

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (eg pregelatinized corn starch, polyvinyl pyrrolidone) or hydroxypropyl methyl cellulose); fillers and fillers (eg lactose, microcrystalline cellulose and calcium hydrogen phosphate); lubricants (eg magnesium stearate, talc or silica; disintegrating agents (eg potato starch or sodium starch glycolate); or wetting agents (eg sodium lauryl sulfate). Tablets may be coated by methods well known in the art Liquid formulations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other appropriate vehicle , prior to use, said liquid formulations can be produced by conventional means, with pharmaceutically acceptable additives, such as suspending agents (eg sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (eg lecithin or gum arabic); non-aqueous vehicles (eg almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (eg p-hydroxybenzoate s of methyl or propyl, or sorbic acid). The formulations may also contain buffer salts, flavoring, flavoring, coloring and sweetening agents, as appropriate.
appropriate.

Formulations for administration via oral can be formulated appropriately to provide a controlled release of active compound.

For oral administration, the Composition can take the form of tablets or can be formulated in a conventional way.

The compounds of the invention can be formulated for parenteral administration by bowling injection or by continuous infusion. Formulations for injection can be present in a unit dosage form, eg in ampoules or in multi-dose containers, with a preservative agent added. The compositions may take such forms as suspensions, solutions or emulsions in oily vehicles or aqueous; and may contain formulation agents such as agents suspensions, stabilizers and / or dispersants; alternatively, the active ingredient may be in a powder form for its constitution with an appropriate vehicle, eg sterile exempt water of pyrogens, before use.

The compounds of formula (I) can be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, sprays or drops (eg drops for eyes, ears or nose). Ointments and creams are they can formulate, for example, with an aqueous or oily base with the addition of appropriate thickening and / or gelling agents. The Ointments for administration to the eyes can be produced from a sterile way, using sterilized components.

Lotions can be formulated with a base watery or oily, and usually will also contain one or more emulsifying agents, stabilizing agents, agents dispersants, suspending agents, thickening agents, or agents dyes The drops can be formulated with an aqueous base or not aqueous, which also comprises one or more dispersing agents, stabilizing agents, solubilizing agents or agents Suspenders They may also contain a preservative.

The compounds of formula (I) can be formulated in rectal compositions such as suppositories or retention enemas, which, for example, contain conventional suppository bases, such like cocoa butter or other glycerides.

The compounds of formula (I) can be formulated as deposit formulations. Such formulations of action prolonged can be administered by implantation (for example by subcutaneous or intramuscular route) or by intramuscular injection. So, for example, the compounds of formula (I) can be formulated with appropriate polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or exchange resins of ions, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

For intranasal administration, the compounds of formula (I) can be formulated in the form of solutions for administration with an appropriate metered dose device or unit, or alternatively as a mixture of powders with a appropriate vehicle for administration using an appropriate supply device

A proposed dose of the compounds of formula (I) is 1 to about 1,000 mg per day. It will be appreciated that it may be necessary to make routine variations in the dosage, depending on the age and condition of the patient, and the exact dosage will ultimately be at the discretion of the doctor or veterinarian attending the patient. The dosage will also depend on the route of administration and the particular compound selected.
I swim.

Therefore, for a route administration parenterally, a daily dose will typically be in the range of 1 to about 100 mg, preferably 1 to 80 mg per day For an oral administration, a daily dose It will typically be in the range of 1 to 300 mg, eg 1 to 100 mg

The compounds of formula (I), and the salts and solvates thereof, can be prepared by the methods generals outlined below. In the next description, the groups R, R 1, R 2, R 4, R 5, R 7, R 8, R 9, R 10, m, n, p, q and r have the previously defined meanings for the compounds of formula (I) unless otherwise stated.

According to the general procedure (A), a compound of formula (I) in which R 4 is hydrogen or a group (CH 2) q R 7 as defined in formula (I), a provided that when R 5 is a C 1-4 alkyl or COR 6 group, R 5 is not in position 3 of the piperazine ring, it can be prepared by reduction of a keto-piperazine of formula (II), in which R4a is hydrogen or an appropriate nitrogen protecting group or R4a is a group (CH2) qR7 or its protective derivatives, followed, when necessary or desired, by the elimination of any of the groups
protectors

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7

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The reaction can be carried out using a appropriate metal reducing agent such as a metal hydride, for example a borane hydride, or a metal hydride complex such as a lithium aluminum hydride, a boron hydride or a organ-metal complex such as borane-methyl sulfide, 9-bora-biciclononano (9-BBN), triethyl silane, sodium triacetoxy borohydride, sodium cyano borohydride.

Alternative boranes can be produced in situ by reacting sodium borohydride in the presence of iodine, with an inorganic acid (eg sulfonic acid) or an organic acid such as formic acid, trifluoroacetic acid, acetic acid or methanesulfonic acid.

Suitable solvents for this reaction are ethers (eg tetrahydrofuran), or a halogenated hydrocarbon (e.g. dichloromethane) or an amide (e.g. N, N-dimethylformamide) to an a temperature within the range from the temperature ambient to reflux temperature of the mixture of reaction.

The compounds of formula (II) can be prepare by treating compounds of formula (III) in which R 4a and R 5 have the meaning defined in formula (II)

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8

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with triphosgene, within a aprotic solvent such as dichloromethane and in the presence of a organic base such as triethyl amine, to form the intermediate carbonyl chloride (IV) compound that can be isolate if required, followed by a reaction of compound (IV) with the amine compound (V)

9

The reaction conveniently takes place in the sine of an aprotic solvent, such as a hydrocarbon, a halogenated hydrocarbon such as dichloromethane or an ether such as tetrahydrofuran, optionally in the presence of such a base as a tertiary amine, e.g. diisopropyl ethyl amine.

The compounds of formula (III) can be prepare by reducing a dihydropyrazine-2-one (VI) using a Appropriate metal reducing agent, such as sodium borohydride. Alternatively, a catalytic hydrogenation can be used, by example using a palladium or carbon catalyst, within a suitable solvent such as methanol.

10

Alternative compounds of formula (III), in the that R 5 is hydrogen, can be prepared by reaction of compounds of formula (VII), wherein R 11 is an alkyl group C_ {1-4} and X is an appropriate labile group such as a halogen, namely a bromine or iodine atom, or OSO_ {2} CF_ {3}.

eleven

with ethylenediamine. The reaction conveniently takes place within an appropriate solvent, such as an alcohol (namely ethanol) at a temperature high.

According to another general procedure (B), a compound of formula (I) in which R 4 is hydrogen or (CH2) rCO (CH2) pR7 as defined previously it can be prepared by reacting a compound of formula (VIII)

12

wherein R 4b represents a nitrogen protecting group or R 4b is (CH 2) rCO (CH 2) pR 7 or its protective group, with triphosgene within an aprotic solvent such as dichloromethane or alkyl esters (eg ethyl acetate), and in the presence of an organic base such as triethyl amine, to form the intermediate carbonyl chloride compound (IVa) which, if required, can be isolate, followed by the reaction of compound (IV) with the compound of
amine (V)

13

The reaction conveniently takes place in the sine of an aprotic solvent, such as a hydrocarbon, a halogenated hydrocarbon such as dichloromethane or an ether such as tetrahydrofuran or alkyl esters (ie, ethyl acetate) optionally in the presence of a base such as an amine tertiary, e.g. diisopropyl ethyl amine or triethyl amine, followed by deprotection when, is necessary.

When R_ {4a} or R_ {4b} is a protective group of nitrogen, examples of appropriate groups include alkoxycarbonyl, e.g. t-butoxycarbonyl, benzyloxycarbonyl, aryl sulfonyl, eg phenyl sulfonyl or 2-trimethylsilyl ethoxymethyl.

Protection and unprotection can be perform using conventional techniques such as those described in the work "Protective Groups in Organic Synthesis [Groups protectors in organic synthesis] 2nd edition "by T.W. Greene and P.G.M. Wuts (John Wiley & Sons, 1991) and as described in The examples presented below.

The compounds of formula (I), in which R4 is a group CO (CH2) pR7 or its protective derivatives, can be prepared by the reaction of compound of formula (I)

14

in which R_ {4} is an atom of hydrogen, with an activated acid derivative R 7 (CH 2) pCO 2 H (IX).

Activated carboxylic acid derivatives (IX) can be prepared by conventional means. Derivatives Suitable carboxylic acid activators include the halide of corresponding acyl, anhydride mixture, activated ester such as the thioester or derivative formed between the carboxylic acid group and a coupling agent such as those used in the chemistry of peptides, for example carbonyl-dimidazole or a resign as 1- (3-dimethylaminopropyl) -3-ethylcarbodimide.

The reaction is preferably carried out in an aprotic solvent such as an amide, for example N, N-dimethylformamide or acetonitrile.

The compounds of formula (I) in which R 4 is CONR_ {9} R_ {8} in which R_ {9} or R_ {8} have the meaning defined in formula (I) can be prepared by reaction of a compound of formula (I) in which R 4 is a hydrogen atom with triphosgene in an aprotic solvent such as dichloromethane and in the presence of an organic base such as triethylamine followed by the reaction with the amine compound NR_ {R} {8} (X).

Alternatively, the compounds of formula (I) in which R_ {4} is a CONHR_ {9} group in which R_ {9} is C 1-4 alkyl can also be prepared by the reaction with the isocyanate of formula R9 NC-O  (XI). The reaction with the compound (XI) is carried out conveniently in a solvent such as tetrahydrofuran or aqueous tetrahydrofuran, a halohydrocarbon (for example, dichloromethane) or acetonitrile optionally in the presence of a base such as triethylamine and at a temperature within the range 0-80 ° C.

In a further embodiment, the compounds of formula (I) in which R 4 is (CH 2) qR 7 or R 4 is (CH 2) rCO (CH 2) pR 7 in which q, r and R_ {7} has the meanings defined in the formula (I) or are its protective derivatives with the proviso that r does not be zero, they can be prepared by the reaction of compounds of formula (I) in which R 4 is a hydrogen group with a compound of formula (XII) R 7 (CH 2) qX or X (CH 2) rCO (CH 2) pR 7 (XIII), wherein X is a leaving group such as halogen, for example a Chlorine, bromine atom, a mesyl or tosyl group.

In a more preferred embodiment, the compounds of formula (I) in which R 4 is (CH 2) q R 7 in those that q and R_ {7} have the meanings defined in the formula (I), or are their protective derivatives, can also be prepared by the reaction of compounds of formula (I) in which R 4 it is a hydrogen group with a compound of formula (XIV) R 7 (CH 2) qCHO (XIV), in which q is zero or a integer from 1 to 3 and R 7 has the defined meanings in formula (I) or are its protective derivatives, in the presence of a suitable metal reducing agent such as NaCNBH 3.

In a more preferred embodiment, the compounds of formula (I) in which R 1 and R 2 together with the atom of nitrogen and carbon to which they are attached respectively represent a heterocyclic group of 5 to 6 unsaturated members can be prepared by ring closure metathesis reaction (RCM) of the compounds of formula (XV).

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fifteen

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catalyzed by a metal complex transitional such as a ruthenium alkylidene complex (it is tell, benzylidene-bis (tricyclohexylphosphine) dichlororutenium). The reaction is conveniently carried out in a solvent. aprotic such as dichloromethane to 0 ° C

The compounds of formula (XV) can be prepared from the appropriate intermediate using any of the processes described in this document to prepare the compounds of formula (I).

The compound of formula (I) in which R1 and R2 together with the nitrogen and carbon atom to which they are joined respectively represent a heterocyclic group of 5 to 6 saturated members can be prepared by reducing the group 5- to 6-membered saturated heterocyclic corresponding to the suitable reducing agent such as by catalytic hydrogenation in a suitable solvent such as methanol at temperature ambient.

When it is desired to isolate a compound of formula (I) in the form of a salt, for example a pharmaceutically salt acceptable, this can be achieved by reacting the compound of formula (I) in the form of the free base with an amount appropriate of a suitable acid and within a suitable solvent such as an alcohol (eg ethanol or methanol), an ester (eg. ethyl acetate), or an ether (eg diethyl ether, tert-butyl methyl ether or tetrahydrofuran).

The compounds of formulas (V), (VI), (VIII), (IX), (X), (XII), (XIII) or (XIV) can be prepared by methods analogous to those used for known compounds.

Thus, for example, compounds can be obtained of formula (VIII) by reduction of a compound of formula (III).

The reaction can be carried out using a appropriate metal reducing agent, such as a metal hydride, for example a borane hydride, or a metal hydride complex such as lithium aluminum hydride, a borohydride, or a complex organ-metallic such as a borane-methyl sulfide, 9-bora-biciclononano (9-BBN), triethyl silane, sodium triacetoxy borohydride, cyano borohydride of sodium.

Alternative boranes can be produced in situ by reacting sodium borohydride in the presence of iodine, with an inorganic acid (eg sulfonic acid) or an organic acid such as formic acid, trifluoroacetic acid and methanesulfonic acid.

Pharmaceutically acceptable salts can be also prepare from other salts, including other salts pharmaceutically acceptable, of the compound of formula (I), using conventional methods

The compounds of formula (I) can be isolated easily in association with solvent molecules by crystallization from an appropriate solvent, or by evaporation of this, to give the corresponding solvates.

When a specific enantiomer of a compound of general formula (I), this can be obtained by example by resolution of a corresponding mixture of enantiomers of a compound of formula (I), using conventional methods.

Thus, specific enantiomers can be prepared of the compounds of formula (I), in which R 4 is an atom of hydrogen, by reaction of an appropriate chiral alcohol, in the presence of a source of a carbonyl group (such as triphosgene or carbonyl diimidazole) separating the resulting diastereoisomeric carbamates by conventional means, e.g. ex. by chromatography or fractional crystallization. Required enantiomer of a compound of general formula (I) can be isolated by elimination of the carbamate radical and conversion into the required free base or salts thereof.

An appropriate chiral alcohol for use in the process includes ( R ) -sec-phenylethyl alcohol, etc.

Alternatively, enantiomers of a compound of general formula (I) can be synthesized from the appropriate optically active intermediates, using any of the general procedures described here.

Thus, for example, the required enantiomer will can be prepared by means of the corresponding enantiomeric amine of formula (III), using any of the procedures before described to prepare compounds of formula (I) from the amine (III). The amine (III) enantiomer can be prepared at starting from racemic amine (III) using procedures conventional, such as salt formation with an appropriate optically active acid such as L (+) - mandelic acid or (1S) - (+) - acid 10-canfo-sulfonic.

In a preferred embodiment of the invention, the specific enantiomer of the amine (IIIa)

16

can be prepared by resolution dynamic kinetics of the amine (III) with an appropriate acid optically active, such as L (+) - mandelic acid or (1S) - (+) - acid 10-canfo-sulfonic in the presence of an aromatic aldehyde such as 3,5-dichloro-salicylic-aldehyde, salicylic aldehyde, benzaldehyde-p-nitro-benzaldehyde.

A preferred aldehyde particularly for its use in this reaction is the 3,5-dichloro-salicylic-aldehyde.

The reaction is carried out in a manner suitable within an aprotic solvent, such as tetrahydrofuran or ethyl acetate, at a temperature that fluctuates between 20 and 60ºC.

The invention is further illustrated by the following Intermediate Compounds and Examples, which are not It is intended to constitute a limitation of the invention.

In the Intermediate Compounds and Examples, a unless otherwise indicated:

Melting points (m.p.) were determined in a device for m.p. of Gallenkamp, and they are uncorrected. All temperatures refer to ºC. The infrared spectra are measured on an FT-IR instrument (infrared with Fourier transform). MRI spectra of protons (1 H-NMR) were recorded at 400 MHz, chemical shifts are reported in ppm downstream (d) at from Me_ {4} Yes, used as internal standard, and assigned as singles (s), doublets (d), doublets of doublets (dd), triplets (t), quartets (q) or multiplets (m). Column chromatography it was carried out on silica gel (Merck AG Darmstaadt, Germany). The following abbreviations are used in the text: AcOEt = ethyl acetate, CH = cyclohexane, DCM = dichloromethane, Et2O = diethyl ether, DMF = N, N'-dimethylformamide, DIPEA = N, N-diisopropyl ethyl amine,  MeOH = methanol, TEA = triethyl amine, TFA = acid trifluoroacetic acid, THF = tetrahydrofuran. Tlc (thin layer chromatography) refers to a thin layer chromatography on silica plates, and the term "dried" refers to a dried solution over anhydrous sodium sulfate; t.a. (TA) refers at room temperature

The enantiomer A or enantiomer B refers to a only enantiomer whose absolute stereochemistry had not been characterized.

The diastereoisomer A refers to a mixture of compounds that have anti configuration , as defined above.

The diastereoisomer B refers to a mixture of compounds having configuration without , as defined above.

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Intermediate compound one

Acid 2-methyl-4-fluoroboronic

To magnesium chips (0.5 g), heated to 90 ° C, a solution of commercial 2-bromo-5-fluorotoluene (2 mL) in THF (3 mL) was added dropwise. The reaction mixture was heated at 90-95 ° C for 1 1/2 h, and then the mixture was diluted with more THF (10 mL) and transferred into an addition funnel. The last solution and trimethylborate (2.1 mL) were added simultaneously to stirred Et 2 O (15 mL), keeping the temperature below -60 ° C. The reaction mixture was allowed to warm to rt, then stirring was continued for 1 1/2 h. Water (6 mL) was added and the reaction mixture was stirred overnight. AcOEt was added and the solution was washed with 1N HCl and brine. The organic phase was then dried and concentrated to give the unpurified product that was triturated in Et2O / petroleum (25 ml / 75 mL) to obtain the title compound as a trimer (1.44 g, powder
White).

NMR (DMSO) δ (ppm) 7.87 (m, 3H), 6.99-6.93 (m, 6H), 2.6 (s, 9H).

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Intermediate compound 2

2- (4-Fluoro-2-methyl-phenyl) -pyrazine

A mixture of intermediate 1 (1.34 g), 2-chloropyrazine (1 mL) and bis [1,2-bis (diphenylphosphino) ethane] -palladium (0) (0.21 g) in toluene / sol. of 1M Na2CO3 / 95% EtOH 20 mL / 20 mL / 10 mL was heated at reflux for 2 h. The solution was poured into AcOEt and washed with brine. The organic phase was then dried and concentrated to give the product without purification, which was purified by flash chromatography (CH / AcOEt 85:15) to obtain the title compound (1.4 g) as a white powder.

m.p. = 66-68 ° C;

NMR (DMSO) δ (ppm) 8.81 (d, 1H), 8.72 (m, 1H), 8.63 (d, 1H), 7.52 (m, 1H), 7.22 (m, 1H), 7.17 (m, 1H), 2.35 (s, 3H).

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Intermediate compound 3

2- (3-Isopropyl-phenyl) -pyrazine

To a solution of commercial 3-isopropyl-benzene boronic acid (1.0 g) in a 2: 2: 1 mixture of toluene / 1M Na 2 CO 3 / EtOH (122 mL), at rt, were added 2-chloropyrazine (599 µL) and the bis [1,2-bis (diphenylphosphino) ethane] -palladium (0) catalyst (110 mg). The reaction mixture was heated at 80 ° C for 3 h. It was then cooled and divided between AcOEt / NaCl aq. sat. The phases were separated and the organic layer was dried. The solids were filtered and the solvent was evaporated. The unpurified oil was purified by flash chromatography (CH / AcOEt 7: 3) to obtain the title compound as a clear oil (468 mg).

NMR (CDCl3): δ (ppm) 9.02 (d, 1H), 8.63 (m, 1H), 8.49 (d, 1H), 7.89 (m, 1H), 7.80 (m, 1H), 7.44 (t, 1H), 7.35 (d, 1H), 3.02 (m, 1H), 1.31 (d, 6H).

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Intermediate compound 4

2- (2-Isopropyl-phenyl) -pyrazine

1) To a suspension of magnesium chips (134 mg) in THF anh. (2.5 mL), at t.a., in N2, a small was added crystal of I 2, followed by 10% of a solution of 1-bromo-2-isopropyl benzene commercial (1.0 g) in THF anh. (2.6 mL). The suspension was heated gently (hot air gun) until the Brown color. The remaining bromide was added drop by drop, keeping the reaction mixture warm (50-60 ° C)  With an oil bath. After the addition was complete (15 min) the suspension was stirred at 60 ° C until the chips were magnesium had reacted almost completely (2 h). The new one Brown solution was used in the next stage.

2) To a solution of 2-chloropyrazine (448 µL) in THF anh. (5.1 mL), at 0 ° C, in N 2, [1,2-bis (diphenylphosphino) ethane] dichloro-nickel (II) (100 mg) and Grignard reagent were added successively dropwise. The brown solution was stirred at rt for 30 min, then at reflux for 3 h. It was then poured into NaCl / DCM ac. sat. and the phases were separated. The aqueous layer was extracted with DCM (2x) and the combined organic extracts were dried. The solids were filtered and the solvent was evaporated. The unpurified oil obtained was purified by flash chromatography (CH / AcOEt 7: 3) to obtain the title compound as a yellow oil (676 mg).

NMR (CDCl3): δ (ppm) 8.67 (d, 1H), 8.67 (m, 1H), 8.54 (d, 1H), 7.5-7.3 (m, 4H), 3.13 (m, 1H), 1.20 (d, 6H).

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Intermediate compound 5

2- (4-Fluoro-3-methyl-phenyl) -pyrazine

1) To a suspension of magnesium chips (167 mg) in THF anh. (2.6 mL), at t.a., in N2, a small was added crystal of I 2, followed by 10% of a solution of 4-Bromo-1-fluoro-2-methyl-benzene commercial (1.0 g) in THF anh. (2.7 mL). The suspension was heated gently (hot air gun) until the Brown color. The remaining bromide was added drop by drop, keeping the reaction mixture warm (50-60 ° C)  With an oil bath. After the addition was complete (15 min) the suspension was stirred at 60 ° C until the chips were magnesium had reacted almost completely (2 h). The new one Brown solution was used in the next stage.

2) To a solution of 2-chloropyrazine (472 µL) in THF anh. (5.3 mL), at 0 ° C in N 2, [1,2-bis (diphenylphosphino) ethane] dichloro-nickel (II) (100 mg) and the Grignard reagent were added successively dropwise. The brown solution was stirred at rt for 30 min, then at reflux for 3 h. It was then poured into NaCl / DCM ac. sat. and the phases were separated. The aqueous layer was extracted with DCM (2x) and the combined organic extracts were dried. The solids were filtered and the solvent was evaporated. The unpurified oil obtained was purified by flash chromatography (CH / AcOEt 7: 3) to give the title compound as a yellow oil (571 mg).

NMR (CDCl3): δ (ppm) 8.98 (d, 1H), 8.60 (m, 1H), 8.49 (d, 1H), 7.87 (m, 1H), 7.80 (m, 1H), 7.13 (t, 1H), 2.37 (s, 3H).

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Intermediate compound 6

2- (2,4-Difluoro-phenyl) -pyrazine

1) To a suspension of magnesium chips (139 mg) in THF anh. (2.6 mL), at t.a., in N2, a small crystal of I2, followed by 10% of a solution of 1-Bromo-2,4-difluoro-benzene commercial (1.0 g) in THF anh. (2.6 mL). The suspension was heated gently (hot air gun) until the Brown color. The remaining bromide was added drop by drop, keeping the reaction mixture warm (50-60 ° C)  With an oil bath. After the addition was complete (15 min) the suspension was stirred at 60 ° C until the chips were magnesium had reacted almost completely (2 h). The new one Brown solution was used in the next stage.

2) To a solution of the 2-chloropyrazine (463 µL) in THF anh. (5.2 mL), to 0 ° C, in N 2, were added successively drop by drop [1,2-bis (diphenylphosphino) ethane] dichloro-nickel (II) (50 mg) and Grignard reagent. The brown solution was agitated to t.a. for 30 min, then at reflux for 3 h. After It was poured into NaCl / DCM ac. sat. and the phases were separated. The aqueous layer was extracted with DCM (2x) and organic extracts combined were dried. The solids were filtered and the solvent was evaporated. The unpurified oil obtained was purified by flash chromatography (CH / AcOEt 7: 3) to give the title compound as a yellow solid (175 mg).

NMR (CDCl3): δ (ppm) 9.01 (dd, 1H), 8.78 (dd, 1H), 8.66 (d, 1H), 7.99 (td, 1H), 7.47 (td, 1H), 7.29 (td, 1H).

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Intermediate compound 7

Hydrochloride 2- (4-Fluoro-2-methyl-phenyl) -piperazine

A two round bottom flask was equipped mouths with a water condenser and an addition funnel and it was purged with N2. Mg shavings (1.45 g) were introduced into the flask and were suspended in THF anh. (5 mL). A little Crystal of I 2 was added to activate Mg. The funnel of addition was filled with a solution of 2-Bromo-5-fluorotoluene commercial (10 g) in THF anh. (30 mL). The bromide solution was added dropwise to the Mg chips and the solution was heated to about 70 ° C. The solution was maintained at this temperature until the complete disappearance of the Mg shavings.

Meanwhile, it was dissolved 2-Chloropyrazine (4.75 mL) in THF anh. (30 mL) and it was added [1,2-bis (diphenylphosphino) ethane] dichloro-nickel  (II) (510 mg). To this suspension, the Grignard reagent, at 0 ° C, in N2. After the addition was complete, the reaction mixture was heated to reflux for 2 h. THF was evaporated, the residue was poured into NaCl sat. ac. and the aqueous phase was extracted with DCM (3x). Extracts organic were dried, solids were filtered and the solvent was evaporated. The unpurified oil was purified by flash chromatography (CH / AcOEt 85:15) and then through a small column of Florisil (eluent: DCM) to remove the residue nickel (6.0 g): was obtained 2- (4-Fluoro-2-methyl-phenyl) -pyrazine (6.0 g) as a solid yellow stick.

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2- (4-Fluoro-2-methyl-phenyl) -pyrazine (0.3 g) dissolved in 95% EtOH (20 mL) and 37% HCl (0.2 mL) was hydrogenated at 5 atm. for 4 h, in the presence of 20% Pd (OH) 2 / C (30 mg) as catalyst. The catalyst was filtered and the solvent was evaporated. The unpurified residue was triturated in MeOH / AcOEt (5 mL / 15 mL) to obtain the title compound (0.08 g) as a white powder.

m.p. > 22 ° C;

NMR (DMSO) δ (ppm) 9.72 (width, 2H), 7.90 (d, 1H), 7.21-7.17 (m, 2H), 4.85 (m, 1H), 3.57-3.2 (m, 6H), 2.40 (s, 3H).

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Intermediate compound 8

Acid benzyl ester 3- (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 7 (0.25 g) and TEA (0.5 mL) in DCM (15 mL) was added dropwise a solution of benzylchloroformate (0.15 mL) in DCM (10 mL), at 0 ° C The reaction mixture was stirred at 0 ° C for 2 h, then washed with brine. The organic phase was dried and concentrated to give the product without purification, which was purified by flash column chromatography (CH / AcOEt 25:75) to obtain the title compound (0.21 g) as a colorless oil.

NMR (CDCl 3, 40 ° C) δ (ppm) 7.52 (m, 1H), 7.4-7.3 (m, 5H), 6.9-6.8 (m, 2H), 5.16 (dd, 2H), 4.12 (m, 2H), 3.86 (m, 1H), 3.3-2.7 (m, 4H), 2.33, (s wide, 3H).

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Intermediate compound 9

Acid benzyl ester 3- (3-Isopropyl-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 3 (428 mg) in EtOH anh. (47 mL), at rt, in N 2, conc. HCl were added. (492 µL) and 20% Pd (OH) 2 / C (86 mg, 20% by weight). The black suspension was placed in a PARR apparatus and hydrogenation was done at rt under 7 atm of H2 for 18 h. The catalyst was then filtered on Celite and the Celite cake was rinsed with MeOH. The filtrate was evaporated until it was dry. The solid gray 2- (3-isopropyl-phenyl) -piperazine hydrochloride (654 mg) was dissolved in DCM anh. (24 mL), at 0 ° C, in N 2, then TEA (1.32 mL) and benzylchloroformate (404 µL) were added. The solution was stirred at 0 ° C for 2 1/2 h. It was then poured into DCM / NaCl aq. sat./K_{2}CO_{3} ac. sat. and the phases were separated. The aqueous layer was extracted with DCM (1x) and the combined organic extracts were dried. The solids were filtered and the solvent was evaporated. The unpurified oil was purified by flash chromatography (CH / AcOEt 6: 4) to give the title compound as a yellow oil (192 mg).

NMR (CDCl3): δ (ppm) 7.34-7.12 (m, 8H), 5.08 (m, 2H), 3.89 (broad d, 1H), 3.85 (wide m, 1H), 3.55 (wide d, 1H), 3.0-2.65 (m wide, 6H), 1.17 (d, 6H).

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Intermediate compound 10

Acid benzyl ester 3- (2-Isopropyl-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 4 (315 mg) in EtOH anh. (40 mL), at rt, in N 2, conc. HCl was added. (529 µL) and Pd (OH) 2 / C 20% (63 mg, 20% by weight). The black suspension was placed in a PARR apparatus and hydrogenation was done at rt under 7 atm of H2 for 18 h. The catalyst was then filtered on Celite and the Celite cake was rinsed with MeOH. The filtrate was evaporated until it was dry. The gray solid 2- (2-isopropyl-phenyl) -piperazine hydrochloride (411 mg) was dissolved in DCM anh. (16 mL), at 0 ° C, in N 2, then TEA (886 µL) and benzylchloroformate (272 µL) were added. The solution was stirred at 0 ° C for 2.5 h. It was then poured into DCM / NaCl aq. sat./K_{2}CO_{3} ac. sat. and the phases were separated. The aqueous layer was extracted with DCM (1x) and the combined organic extracts were dried. The solids were filtered and the solvent was evaporated. The unpurified oil was purified by flash chromatography (CH / AcOEt 6: 4) to obtain the title compound as a yellow oil (117 mg). NMR (CDCl3): δ (ppm) 7.52 (d, 1H), 7.4-7.3 (m, 5H), 7.26 (d, 1H), 7.21 (t, 1H), 7.14 (t, 1H), 5.14 (d, 1H), 5.03 (d, 1H), 4.0-3.8 (m, 3H), 3.23 (m, 1H ), 2.99 (m, 1H), 2.91 (m, 1H), 2.8-2.0 (m, 2H), 1.19 (d, 6H).

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Intermediate compound eleven

Acid benzyl ester 3- (4-Fluoro-3-methyl-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 5 (314 mg) in EtOH anh. (30 mL), at rt, in N2, conc. HCl were added. (350 µL) and Pd (OH) 2 / C 20% (30 mg, 10% by weight). The black suspension was placed in a PARR apparatus and hydrogenation was done at rt under 7 atm of H2 for 18 h. The catalyst was then filtered on Celite and the Celite cake was rinsed with MeOH. The filtrate was evaporated until it was dry. The gray solid 2- (4-Fluoro-3-methyl-phenyl) -piperazine hydrochloride (411 mg) was dissolved in DCM anh. (15 mL), at 0 ° C, in N 2, then TEA (858 µL) and benzylchloroformate (264 µL) were added. The solution was stirred at 0 ° C for 2.5 h. It was then poured into DCM / NaCl aq. sat./K_{2}CO_{3} ac. sat. and the phases were separated. The aqueous layer was extracted with DCM (1x) and the combined organic extracts were dried. The solids were filtered and the solvent was evaporated. The unpurified oil was purified by flash chromatography (CH / AcOEt 6: 4) to obtain the title compound as a yellow oil (170 mg).

NMR (CDCl3): δ (ppm) 7.3-7.4 (m, 5H), 7.23 (m, 1H), 7.17 (m, 1H), 6.96 (t, 1H), 5.17 (m, 2H), 4.15 (m, 2H), 3.67 (m, 1H), 2.7-3.2 (m, 4H), 2.27 (s, 3H).

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Intermediate compound 12

Acid benzyl ester 3- (2,4-Difluoro-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 6 (175 mg) in EtOH anh. (30 mL), at rt, in N2, conc. HCl were added. (228 µL, 2.5 eq) and Pd (OH) 2 / C 20% (20 mg, 10% by weight). The black suspension was placed in a PARR apparatus and hydrogenation was done at rt under 7 atm of H2 for 18 h. The catalyst was then filtered on Celite and the Celite cake was rinsed with MeOH. The filtrate was evaporated until it was dry. The greenish solid 2- (2,4-difluoro-phenyl) -piperazine hydrochloride (247 mg) was dissolved in DCM anh. (9.1 mL), at 0 ° C, in N 2, then TEA (508 µL) and benzylchloroformate (162 µL) were added. The solution was stirred at 0 ° C for 3 h. It was then poured into DCM / NaCl aq. sat./K_{2}CO_{3} ac. sat. and the phases were separated. The aqueous layer was extracted with DCM (1x) and the combined organic extracts were dried. The solids were filtered and the solvent was evaporated. The unpurified oil was purified by flash chromatography (CH / AcOEt 6: 4) to obtain the title compound as a yellow oil (100 mg).

NMR (CDCl3): δ (ppm) 7.49 (m, 1H), 7.3-7.4 (m, 5H), 6.76-6.8 (m, 2H), 5.16 (s, 2H), 4.15 (m, 2H), 4.03 (m, 1H), 2.8-3.15 (m, 4H).

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Intermediate compound 13

Acid benzyl ester 4 - [(3,5-bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -3- (4-fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid

A solution of triphosgene (0.02 mL) in DCM (10 mL) was added dropwise to a solution of intermediate 8 (0.05 g) and TEA (0.15 mL) in DCM (10 mL) at 0 ° C . The reaction mixture was allowed to warm to rt in 3 h, then DIPEA (0.07 mL) and (3,5-bis-trifluoromethyl-benzyl) -methyl amine hydrochloride (53 mg) were added. The reaction mixture was stirred at reflux for 2 h and at rt overnight, then washed with a 1N solution of HCl and brine. The organic phase was dried and concentrated to give the product without purification, which was purified by flash chromatography (CH / AcOEt 7: 3) to obtain the title compound (0.05 g) as a colorless oil.

NMR (CDCl3) δ (ppm) 7.76 (s, 1H), 7.49 (s, 2H), 7.4-7.3 (m, 5H), 7.20 (dd, 1H), 6.86 (d, 1H), 6.79 (m, 1H), 5.17 (s, 2H), 4.66 (d, 1H), 4.64 (m, 1H), 4.36 (d, 1H), 3.97 (m, 2H), 3.4 (m, 2H), 3.16 (m, 2H), 2.93 (s, 3H), 2.38 (wide s, 3H).

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Intermediate compound 14

Acid benzyl ester 4 - [(3,5-bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -3- (3-isopropyl-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 9 (192 mg) in DCM anh. (7 mL), at 0 ° C, in N2, TEA (237 was added µL). Then, a triphosgene solution was added dropwise (76 mg) in DCM anh. (4 mL). The reaction was stirred at 0 ° C for 2 h.

To this solution were added DIPEA (198 µL) and (3,5-bis-trifluoromethyl-benzyl) -methyl amine hydrochloride (200 mg). The solution was stirred at rt for 18 h. The reaction mixture was diluted with DCM, washed with 10% citric acid (1x) and dried. The solids were filtered and the solvent was evaporated. The unpurified oil was purified by flash chromatography (CH / AcOEt 65:35) to give the title compound as a thick oil (353 mg).

NMR (CDCl3): δ (ppm) 7.91 (broad s, 1H), 7.84 (broad s, 2H), 7.36-7.26 (m, 5H), 7.18-7.10 (m, 2H), 7.06 (m, 2H), 5.07 (s, 2H), 4.76 (t, 1H), 4.50 (broad s, 2H), 3.96 (dd, 1H), 3.66 (td, 1H), 3.57 (dd,  1H), 3.4-3.3 (m, 2H), 3.19 (m, 1H), 2.86 (s, 3H), 2.76 (m, 1H), 1.09 (2d, 6H).

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Intermediate compound fifteen

Acid benzyl ester 4 - [(3,5-bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -3- (2-isopropyl-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 10 (46 mg) in DCM anh. (3.9 mL), at 0 ° C, in N2, TEA (145 µL), then a triphosgene solution was added dropwise (46 mg) in DCM anh. (3 mL). The reaction was stirred at 0 ° C for 2 h.

To this solution, DIPEA (121 µL) and (3,5-bis-trifluoromethyl-benzyl) -methyl amine hydrochloride (122 mg) were added. The solution was stirred at rt for 18 h. The reaction mixture was diluted with DCM, washed with 10% citric acid (1x) and dried. The solids were filtered and the solvent was evaporated. The unpurified oil was purified by flash chromatography (CH / AcOEt 7: 3) to give the title compound as a clear oil (108 mg).

NMR (CDCl3): δ (ppm) 7.89 (broad s, 1H), 7.71 (broad s, 2H), 7.38-7.28 (m, 5H), 7.28 (dd, 1H), 7.23 (dd, 1H), 7.16 (dt, 1H), 7.01 (dt, 1H), 5.14 (d, 1H), 5.05 (broad d, 1H), 4.68 (dd, 1H), 4.52 (2d (AB), 2H), 3.83 (dd, 1H), 3.71 (dt, 1H), 3.53 (md, 1H), 3.41 (dt, 1H), 3.26 (m, 1H), 3.15-3.05 (m, 2H), 1.19 (d, 3H), 1.13 (m, 3H).

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Intermediate compound 16

Acid benzyl ester 4 - [(3,5-bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -3- (4-fluoro-3-methyl-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 11 (170 mg) in DCM anh. (7 mL), at 0 ° C, in N2, TEA (217 was added µL). Then, a triphosgene solution was added dropwise (69 mg) in DCM anh. (3 mL). The reaction was stirred at 0 ° C for 2 h.

To this solution were added DIPEA (181 µL) and (3,5-bis-trifluoromethyl-benzyl) -methyl amine hydrochloride (183 mg). The solution was stirred at rt for 18 h. The reaction mixture was diluted with DCM, washed with 10% citric acid (1x) and dried. The solids were filtered and the solvent was evaporated. The unpurified oil was purified by flash chromatography (CH / AcOEt 65:35) to give the title compound as a gummy solid (226 mg).

NMR (CDCl3): δ (ppm) 7.77 (m, 1H), 7.60 (m, 2H), 7.3-7.4 (m, 5H), 7.05-7.15 (m, 2H), 6.90 (m, 1H), 5.14 (m, 2H), 4.6-4.8 (m, 1H), 4.54 + 4.47 (AB, 2H), 3.82 (m wide, 1H), 3.73 (dd, 1H), 3.65 (m, 1H), 3.57 (m, 1H), 3.33 (m, 1H), 3.26 (m, 1H), 2.90 (s, 3H), 2.19 (s, 3H).

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Intermediate compound 17

Acid benzyl ester 4 - [(3,5-bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -3- (2,4-difluoro-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 12 (95 mg) in DCM anh. (3 mL), at 0 ° C, in N 2, TEA (120 µL). Then a triphosgene solution was added dropwise (38 mg) in DCM anh. (3 mL). The reaction was stirred at 0 ° C for 2 h.

To this solution were added DIPEA (100 µL, 2 eq) and (3,5-bis-trifluoromethyl-benzyl) -methyl amine hydrochloride (101 mg). The solution was stirred at rt for 18 h. The reaction mixture was diluted with DCM, washed with 10% citric acid (1x) and dried. The solids were filtered and the solvent was evaporated. The unpurified oil was purified by flash chromatography (CH / AcOEt 7: 3) to give the title compound as a yellow gum (134 mg).

NMR (CDCl3): δ (ppm) 7.76 (s, 1H), 7.56 (s, 2H), 7.26-7.40 (m, 6H), 6.76 (m, 2H), 5.17 (m, 2H), 4.83 (m, 1H), 4.36-4.60 (dd + m, 2H), 3.90 (m, 1H), 3.25-3.7 (m, 2H), 2.86 (s, 3H).

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Intermediate compound 18

Acid benzyl ester 4- (3,5-bis-trifluoromethyl-benzyl-carbamoyl) -3- (4-fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 8 (0.15 g) and TEA (0.32 ml) in DCM (35 ml), a solution of triphosgene (0.065 ml) in DCM (25 ml) was added dropwise at 0 ° C. The reaction mixture was allowed to warm to rt in 3 h, then pyridine (0.3 mL) and 3,5-bis (trifluoromethyl) -benzyl-1-methyl-amine hydrochloride (53 mg) were added. The reaction mixture was stirred at rt overnight, then washed with a 1N solution of HCl and brine. The organic phase was then dried and concentrated to give the unpurified product that was purified by flash chromatography (CH / AcOEt 7: 3) to obtain the title compound (0.086 g) as a stick yellow oil and 4- chloride. benzyloxycarbonyl-2- (4-fluoro-2-methyl-phenyl) -piperazine-1-carbonyl (0.075 g).

Title compound : NMR (CDCl3) δ (ppm) 78-7.7 (m, 1H), 7.5-7.4 (m, 2H), 7.4-7.25 (m, 5H), 7.20 (m, 1H), 6.95-6.8 (m, 2H), 5.2-5.05 (m, 2H), 4.99 (dd, 1H), 4.6 -4.2 (m, 2H), 4.5-4.15 (m, 2H), 3.8-3.6 (m, 2H), 4.12 (m, 1 / 2H), 3.91 (m, 1 / 2H), 3.61 (m, 1 / 2H), 3.44 (m, 1 / 2H), 2.4-2.2 (s + s, 3H).

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Intermediate compound 19

1- (S) -phenyl-ethyl ester of acid 3- (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid

To a solution of 1,1'-carbonyldimidazole (0.162 g) in DCM (5 mL) was added (S) -sec-phenethyl alcohol (0.122 g). After 30 min., A solution of intermediate 7 (0.180 g) in acetonitrile (5 mL) was added and the mixture was refluxed for 2 h. The mixture was then concentrated to give the product without purification, which was purified by flash chromatography (CH / AcOEt 8: 2) to give the title compound (mixture of diastereomers) (0.180 g) as a foam.

NMR (DMSO) δ (ppm) 7.87 (m, 1H); 7.40-7.25 (m, 5H); 7.02-6.94 (m, 2H); 5.74 (m, 1 H); 3.93-3.71 (m, 3H); 3.00-2.55 (m, 4H); 2.34 (s, 3 H); 2.28 (s, 3 H).

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Intermediate compound twenty

1- (S) -phenyl-ethyl ester of acid 4- (3,5-bis-trifluoromethyl-benzyl-carbamoyl) -3- (R) - (4-fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid  (Diasteréomer 1) (20a) 1- (S) -phenyl-ethyl ester of acid 4- (3,5-bis-trifluoromethyl-benzyl-carbamoyl) -3- (S) - (4-fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid  (Diasteréomer 2) (20b)

A solution of triphosgene (0.075 g) in DCM (5 mL) was added dropwise to a solution of intermediate 19 (0.178 g) and TEA (0.35 mL) in DCM (5 mL) at 0 ° C. After 2 h, DIPEA (0.3 mL) and (3,5-bistrifluoromethylbenzyl) -methyl amine hydrochloride (0.209 g) were added and the mixture was heated to rt after 4 h. DCM was added and the organic phase was washed with 1N HCl (2x10 mL) and brine, dried and concentrated to give the unpurified diastereisomeric mixture. Separation by flash chromatography (CH / AcOEt 8: 2) provided the title compound 20a (0.125 g) and the title compound 20b (0.135 g) as white foams.

Intermediate 20a : NMR (DMSO) δ (ppm) 7.90 (s, 1H); 7.67 (s, 2H); 7.4-7.27 (m, 6H); 6.95 (dd, 1 H); 6.80 (m, 1 H); 5.74 (q, 1 H); 4.60-4.40 (dd, 2H); 4.50 (m, 1 H); 3.79 (m, 3 H); 3.00 (m, 3 H); 2.87 (s, 3 H); 2.29 (s, 3 H); 1.46 (d, 3 H).

Intermediate 20b : NMR (DMSO) δ (ppm) 7.90 (s, 1H); 7.67 (s, 2H); 7.37-7.24 (m, 6H); 6.95 (dd, 1 H); 6.81 (m, 1 H); 5.75 (q, 1 H); 4.60-4.41 (dd, 2H); 4.52 (m, 1 H); 3.83-3.00 (m, 6H); 2.88 (s, 3 H); 2.33 (s, 3 H); 1.48 (d, 3 H).

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Intermediate compound twenty-one

[1- (2,4-Bis-trifluoromethyl-phenyl) -ethyl] -methyl-amine

To a 2M solution of MeNH2 in MeOH (10 ml) was added commercial 3,5-bis (trifluoromethyl) -acetophenone (2.1 g). After 12 h, the mixture was cooled to 0 ° C and then NaBH 4 (0.512 g) was added. After 1 h, the mixture was quenched with H2O and extracted with DCM. Then, the organic phase was dried and concentrated to give the crude product, which was purified by distillation to obtain the title compound (1.5 g) as an oil.

NMR (CDCl3) δ (ppm) 7.8 (m, 3H); 3.8 (q, 1H); 2.4 (s, 3H); 1.4 (d, 3H).

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Intermediate compound 22

Benzyl Acid Ester 4 - {[1- (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-carbamoyl} -3- (4-fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid (mixture of enantiomers A, B) (22a) Benzyl Acid Ester 4 - {[1- (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-carbamoyl} -3- (4-fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid (mixture of enantiomers C, D) (22b)

To a solution of 4-benzyloxycarbonyl-2- (4-fluoro-2-methyl-phenyl) -piperazine-1-carbonyl chloride (0.075 g) in DCM (5 ml) was added DIPEA (0.12 ml) and intermediate 1 (0.1 g). The mixture was refluxed for 2 h, then acetonitrile (5 ml) was added and the solution obtained was heated to 70 ° C, and the mixture was stirred overnight. Then the mixture was concentrated and the residue was dissolved in AcOEt. The organic phase was washed with 1 N HCl and brine, and dried. The organic phase was concentrated to give the crude mixture of diastereoisomeric compounds, which were separated by flash chromatography (with a mixture of CH and AcOEt 8: 2) to obtain the title compound 22a (0.05 g) and the compound of title 22b (0.55 g) as white foams.

intermediate 22a : NMR (CDCl3) δ (ppm) 7.78 (s, 1H); 7.58 (s, 2H); 7.4-7.3 (m, 5H); 7.18 (m, 1 H); 6.86 (m, 1 H); 6.77 (m, 1 H); 5.45 (m, 1 H); 5.16 (s, 2H); 4.6 (m, 1 H); 3.94 (m, 2H); 3.44-3.10 (m, 4H); 2.68 (s, 3 H); 2.4 (s, 3H); 1.49 (d, 3 H).

intermediate 22b : NMR (CDCl3) δ (ppm) 7.75 (s, 1H); 7.53 (s, 2H); 7.4-7.3 (m, 5H); 7.18 (m, 1 H); 6.87 (m, 1 H); 6.78 (m, 1 H); 5.59 (m, 1 H); 5.18 (s, 2H); 4.59 (m, 1 H); 3.97 (m, 2H); 3.44-3.06 (m, 4H); 2.78 (s, 3 H); 2.37 (s, 3 H); 1.53 (d, 3H).

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Intermediate compound 2. 3

Acid methyl ester (4-fluoro-2-methyl-phenyl) -oxo-acetic

1) To a suspension of magnesium chips (617 mg) in anhydrous THF (6 ml) at t.a., under N2, a small crystal of I 2, followed by 10% of a solution of 2-Bromo-5-fluoro-toluene commercial (4.0 g) in anhydrous THF (15 ml). The suspension was heated gently (with a heat gun) until the Dun. The remaining bromide solution was added dropwise, keeping the reaction mixture warm (50-60ºC) with an oil bath. After that the addition was completed (for 15 min), the suspension was stirred at 70 ° C until the magnesium chips had reacted almost completely (2 h). The new brown solution was used in the Next operation

2) A solution of LiBr (4.41 g) in anhydrous THF (50 ml) was added dropwise to a suspension of CuBr (3.64 g) in anhydrous THF (50 ml). The mixture was stirred at rt for 1 h (dark green solution with a small amount of a white solid material in suspension). The Grignard solution, prepared previously, was then added dropwise (an ice bath was used to maintain the temperature <25 ° C) followed by methyl oxalyl chloride (1.95 ml). The reaction mixture was stirred at rt for 2 h. THF was evaporated and the residue was taken up in AcOEt. The organic layer was washed with a saturated aqueous solution of NH 4 Cl (2 x) and dried. The solid materials were filtered and the solvent was evaporated to give a crude oil, which was purified by flash chromatography (mixture of CH and AcOEt 95: 5) to obtain the title compound as a clear oil (2.44 g) .

NMR (CDCl3) δ (ppm) 7.74 (m, 1H); 6.98-7.04 (m, 2H); 3.96 (s, 3 H); 2.61 (s, 3 H).

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Intermediate compound 24

Acid methyl ester (4-fluoro-phenyl) -oxo-acetic

A magnesium chips (0.066 g), previously heated to 90 ° C and covered by THF (1 mL), a iodine crystal followed by a commercial solution 4-fluoro-bromobenzene (0.437 g) in THF (4 mL). The temperature was maintained at 60 ° C until it was completed the metal consumption. The derivative solution Organometallic was added dropwise in a CuBr solution (0.356 g) and LiBr (0.431 g) in THF (10 mL), previously prepared at 0 ° C

At the end of the addition, methyl oxalyl chloride (0.225 mL) was added via a syringe path and the reaction mixture was stirred 2 hr, before being poured into a saturated aqueous solution of NH4Cl and extracted with Et2O. The organic phase was washed with brine and dried. The unpurified product obtained after evaporation of solvents was purified by column chromatography (CH / AcOEt 95: 5) to provide the title compound (0.2 g) as a solid.

1 H-NMR (CDCl 3): δ (ppm): 8.12 (m, 2H), 7.20 (m, 2H), 3.99 (s, 3H).

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Intermediate compound 25

3- (4-Fluoro-2-methyl-phenyl) -5,6-dihydro-1H-pyrazin-2-one

To a solution of intermediate 23 (2.01 g) and ethylene diamine (684 µl) in toluene (40 ml) at rt under N 2 was added anhydrous Na 2 SO 4 (2 g ). The reaction mixture was heated at reflux for 6 h. Then it cooled to the ta and filtered. Solid materials were rinsed with DCM. The solvent was evaporated and the crude oil was purified by flash chromatography (with AcOEt) to give the title compound as a white solid material (1.29 g).

NMR (CDCl3) δ (ppm) 7.33 (m, 1H); 6.95-6.90 (m, 2H); 6.56 (m, 1 H); 3.97 (m, 2H); 3.58 (m, 2H); 2.31 (s, 3 H).

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Intermediate compound 25th

3- (4-Fluoro-2-methyl-phenyl) -piperazin-2-one

To a solution, at 25 ° C, of intermediate 25 (168 g) in methanol (2,400 ml) under nitrogen, 10% Pd / C (44 g) was added. The reaction mixture was placed under an H2 atmosphere and stirred at 25 ° C for approximately 16 hours (until no additional hydrogen was consumed, and the reaction was completed by TLC, with a mixture of EA and MeOH 9/1). The catalyst was filtered under a nitrogen atmosphere and the solvent was removed to a low volume (360 ml), and then methanol (2,040 ml) and ethyl acetate (9,600 ml) were added and silica pad filtration was performed. (800 g); the eluted solution was concentrated to obtain the title compound
(168 g).

1 H-NMR (DMSO) δ (ppm) 7.77 (broad m, 1H); 7.24 (dd, 1 H); 6.96 (dd, 1 H); 6.92 (td, 1 HOUR); 4.43 (s, 1 H); 3.30 (m, 1 H); 3.14 (m, 1 H); 2.92 (m, 1 H); 2.82 (m, 2H); 2.33 (s, 3 H).

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Intermediate compound 26

3- (4-Fluoro-phenyl) -5,6-dihydro-1H-pyrazin-2-one

Intermediate compound 24 (0.190 g) was dissolved in dry toluene (5 mL) under an inert atmosphere; ethylenediamine (0.072 mL) was added dropwise followed by Na2SO4 (0.2 g) and the reaction mixture was refluxed 2 h. The solids were filtered and the unpurified product obtained after evaporation of the solvent was purified by flash chromatography (AcOEt / MeOH 9: 1) to give the title compound (0.155 g as a white solid).

m.p. 118-120 ° C;

1 H-NMR (CDCl 3) δ (ppm): 7.96 (m, 2H), 7.08 (m, 2H), (broad s, 1H), 3.96 (t, 2H), 3.54 (m, 2H).

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Intermediate compound 27

Acid methyl ester bromine- (2,4-dichloro-phenyl) -acetic acid

To a stirred solution of commercial 2,4-dichlorophenylacetic acid (2 g) in DCM (50 mL), DMF (0.1 mL) and oxalyl chloride (1.7 mL) were added and the reaction mixture was heated to reflux for 1/2 h. The solvent was evaporated and the unpurified compound was dissolved in carbon tetrachloride (40 mL). N-Bromosuccinimide (1.8 g) and 2,2'-azobis (2-methylpropionitrile) (0.1 g) were added and the reaction mixture was heated to reflux and irradiated for 2 h. After cooling, methanol (50 mL) was added and the reaction mixture was stirred for 1 h. The solution was concentrated, diluted with AcOEt and washed with 3N HCl and brine. The organic phase was dried and concentrated to give an unpurified residue, which was purified by flash chromatography (CH / AcOEt 9: 1) to obtain a mixture of the title compound and methyl ester of 2,4-dichlorophenyl acetic acid. (1.3 g). This mixture was dissolved in carbon tetrachloride (20 mL) then N-bromosuccinimide (0.89 g) and 2,2'-azobis (2-methylpropionitrile) (0.05 g) were added and the reaction mixture was heated to reflux and was irradiated for 3 1/2 h. The solution was concentrated, diluted with AcOEt and washed with a saturated solution of Na2CO3 and brine. The organic phase was dried and concentrated to give an unpurified residue that was purified by flash column chromatography (CH / AcOEt; 9: 1) to provide the title compound (1.14 g, yellow stick oil).

NMR (CDCl3): δ (ppm) 7.72 (d, 1H), 7.40 (d, 1H), 7.30 (dd, 1H), 5.84 (s, 1H), 3.81 (s, 3H).

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Intermediate compound 28

Acid methyl ester bromine- (3,4-dichloro-phenyl) -acetic acid

DMF (0.1 ml) and oxalyl chloride (1.7 ml) were added to a solution of commercial 3,4-dichlorophenylacetic acid (2 g) in DCM (100 ml) and the reaction mixture was heated at reflux for 1 1/2 h. After cooling, methanol (50 mL) was added and the reaction mixture was stirred for 1 h. The solvent was evaporated and the unpurified compound was purified by flash chromatography (CH / AcOEt 9: 1) to obtain the methyl ester that was dissolved in carbon tetrachloride (60 mL). N-Bromosuccinimide (2.06 g) and 2,2'-azobis (2-methylpropionitrile) (0.2 g) were added and the reaction mixture was heated to reflux and irradiated for 2 h. The solution was concentrated, diluted with ethyl acetate and washed with a saturated solution of Na2CO3 and brine. The organic phase was then dried with Na 2 SO 4 and concentrated to give an unpurified residue that was purified by flash chromatography (CH / AcOEt 9: 1) to obtain the title compound (2.0 g ) as an oil.

NMR (CDCl3) δ (ppm) 7.70 (s, 1H), 7.45 (m, 1H), 5.25 (s, 1H), 3.80 (s, 3H).

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Intermediate compound 29

3- (2,4-Dichloro-phenyl) -piperazine-2-one

To a solution of intermediate 27 (1.14 g) in EtOH (20 mL) were added sodium ethoxide (0.34 g) and ethylenediamine (0.54 mL) and the reaction mixture was stirred at rt for 15 h . The solvent was evaporated and the residue was purified by flash chromatography to provide the title compound (0.35 g) as a white foam.

NMR (DMSO): δ (ppm) 7.87 (width, 1H), 7.55 (d, 1H), 7.41, 7.37 (d + dd, 2H), 4.63 (s, 1H), 3.32, 3.14 (m + m, 2H), 3.02-2.90, 2.84 (m + m, 3H).

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Intermediate compound 30

3- (3,4-Dichloro-phenyl) -piperazine-2-one

To a solution of intermediate 28 (20 g) in EtOH (100 ml) were added sodium ethoxide (0.60 g) and ethylenediamine (0.95 ml) and the reaction mixture was stirred at rt for 15 h. The solvent was evaporated and the residue was diluted with ethyl acetate and washed with brine. The organic phase was dried and concentrated to give the title compound (2.0 g) as a white foam).

NMR (CDCl3): δ (ppm) 7.60 (d, 1H), 7.42 (d, 1H), 7.32, (dd, 1H), 5.91 (sa, 1H), 4.53 (s, 1H), 3.6-3.1 (m + m, 4H).

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Intermediate compound 31

Chloride 3-oxo-2-phenyl-piperazine-1-carbonyl

To a stirred solution of triphosgene (0.558 g) in DCM (10 ml) was added pyridine (0.46 mL) at 0 ° C and, after 10 min, 3-phenyl-piperazine-2-one (1 g). The ice bath was removed and the mixture was stirred at room temperature overnight. The mixture was concentrated and the product was purified by flash chromatography (CH / AcOEt 1: 1) to give the title compound (0.253 g) as a foam.

NMR (CDCl3): δ (ppm): 7.45-7.35 (m, 5H); 6.81 (broad s, 1H); 6.61 (s width, 1H); 5.99 (s, 1 H); 4.3-4.2 (m, 1 H); 3.7-3.3 (m, 3H).

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Intermediate compound 32

(3,5-bis-Trifluoromethyl-benzyl) -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -3-oxo-piperazine-1-carboxylic

To a solution of intermediate 25 (63 mg) in MeOH anh. (6.1 mL), at rt, in N2, 10% Pd / C (7 mg, 10% by weight) was added. The reaction mixture was placed under an atmosphere of H2 and stirred at rt for 2 h. The catalyst was filtered (filter paper) and the solvent was evaporated. The unpurified 3- (4-fluoro-2-methyl-phenyl) -piperazin-2-one (64 mg) was dried under high vacuum and dissolved in DCM anh. (4.0 mL), at 0 ° C in N 2, and TEA (85 µL) was added. Then, a solution of triphosgene (37 mg) in DCM anh was added dropwise. (2 mL). The reaction was stirred at 0 ° C for 2 h. To this solution were added DIPEA (107 µL) and N-methyl-bis (trifluoromethyl) -benzylamine hydrochloride (108 mg). The solution was stirred at rt for 18 h. The reaction mixture was diluted with DCM, washed with 1N HCl (1x) and dried. The solids were filtered and the solvent was evaporated. The unpurified product was purified by flash chromatography (AcOEt) to give the title compound as a white solid (93 mg).

NMR (CDCl3): δ (ppm) 7.79 (s, 1H), 7.59 (s, 2H), 7.20 (wide s, 1H), 6.91-6.84 (m1 1H), 6.07 (m, 1H), 5.69 (s, 1H), 4.58-4.47 (dd, 1H), 3.49 (m, 4H), 2.85-2.39 (s, 6H).

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Intermediate compound 33

(3,4-bis-Trifluoromethyl-benzyl) -methyl-amide of the acid 2- (4-Fluoro-phenyl) -3-oxo-piperazine-1-carboxylic

Intermediate compound 26 (0.135 g) was dissolved in MeOH (5 mL) and the temperature was lowered to 0 ° C, then NaBH 4 (0.102 g) was added carefully. After 2 h, the reduction was completed, the solvent was removed under reduced pressure and DCM was added. The organic phase was washed with H2O and brine before being dried over Na2SO4. The unpurified 3- (4-fluoro-phenyl) -piperazin-2-one (0.134 g) was dried under high vacuum and dissolved in anhydrous DCM (5 mL), at 0 ° C and TEA (0.433 mL) was added dropwise ). To this solution was added at 0 ° C a solution of triphosgene (0.09 g) in dry DCM (3 mL), under an inert atmosphere. The temperature was maintained at 0 ° C for 3 h, then DIPEA (0.4 mL) was added followed by 3,5-bistrifluoromethyl methyl amine hydrochloride (0.27 g). The reaction mixture was stirred at rt overnight before being diluted with DCM and washed with a 1N solution of HCl, H2O and brine. The organic phase was dried and the unpurified product obtained after evaporation of the solvent was purified by flash column chromatography (AcOEt) to provide the title compound as a foam (0.2 g).

NMR (DMSO): δ (ppm) 8.14 (broad s, 1H), 7.97 (s, 1H), 7.78 (s, 2H), 7.37 (m, 2H), 7.09 (m, 2H), 5.13 (s, 1H), 4.49 (dd, 2H), 3.5-3.25 (m, 4H), 2.80 (s, 3H).

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Intermediate compound 3. 4

(3,5-bis-Trifluoromethyl-benzyl) -methyl-amide of the acid 3-oxo-2-phenyl-piperazine-1-carboxylic

To a stirred solution of intermediate 31 (0.239 g) in DMF (5 mL) were added DIPEA (0.41 mL) and 3,5-bistrifluoromethyl methyl amine hydrochloride (0.366 g). After 3 h, the mixture was quenched with brine and the aqueous layer was extracted with AcOEt. The organic layer was dried and concentrated under reduced pressure. The product was purified by flash chromatography (AcOEt) to give the title compound (0.429 g).

NMR (CDCl3): δ (ppm): 7.79 (broad s, 1 HOUR); 7.67 (broad s, 2H); 7.50 (d, 2H); 7.35 (m, 3 H); 5.98 (s, 1 H); 5.43 (s, 1 H): 4.63-4.32 (dd, 2 H); 3.88-3.56 (m, 2H); 3.50-3.30 (m, 2H); 2.81 (s, 3 H).

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Intermediate compound 35

(3,5-bis-Trifluoromethyl-benzyl) -methyl-amide of the acid 2- (2,4-Dichloro-phenyl) -3-oxo-piperazine-1-carboxylic acid

To a solution of intermediate 29 (0.33 g) in DCM (30 mL) were added TEA (0.65 mL) and, dropwise, a solution of triphosgene (0.23 g) in DCM (10 mL) . The reaction mixture was stirred at rt for 1 1/2 h then was concentrated and purified by flash chromatography to provide 2- (2,4-dichloro-phenyl) -3-oxo-piperazine-1-carbonyl chloride (0, 3 g, white foam). The latter was dissolved in DCM (30 mL), then DIPEA (0.3 mL) and (3,5-bistrifluoromethylbenzyl) -methyl amide hydrochloride (0.32 g) were added. The reaction mixture was stirred at reflux for 3 h, then washed with a 1N solution of HCl and brine. The organic phase was then dried and concentrated to give the unpurified product that was purified by flash chromatography (from 100% AcOEt to AcOEt / MeOH 8: 2) to obtain the title compound (0.45 g) as a foam.
white

NMR (DMSO) δ (ppm) 8.30 (broad s, 1H), 7.96 (wide s, 1H), 7.73 (wide s, 1H), 7.54 (d, 1H), 7.35, 7.33 (d + dd, 2H), 5.44 (s, 1H), 4.61 (d, 1H), 4.39 (d, 1H), 3.39, 3.25 (m + m, 4H), 2.76 (s, 3H).

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Intermediate compound 36

(3,5-bis-Trifluoromethyl-benzyl) -methyl-amide of the acid 2- (3,4-Dichloro-phenyl) -3-oxo-piperazine-1-carboxylic acid

To a solution of intermediate 30 (0.413 g) in DCM (40 mL) TEA (1.4 mL) and, dropwise, a solution of triphosgene (0.25 g) in DCM (10 mL) was added. The reaction mixture was stirred at rt for 1 1/2 h, then DIPEA (0.6 mL) and (3,5-bistrifluoromethylbenzyl) methyl amine hydrochloride (0.54 g) were added. The reaction mixture was stirred at reflux for 3 h, then washed with a 1N solution of HCl and brine. The organic phase was then dried and concentrated to give the crude product which was purified by flash chromatography (AcOEt 100% to AcOEt / MeOH 8: 2) to give the title compound (0.13 g, white foam) .

NMR (DMSO) δ (ppm) 8.24 (broad s, 1H), 7.96 (s, 1H), 7.75 (s, 2H), 7.54 (d, 1H), 7.51 (d, 1H), 7.33 (dd, 1H), 5.11 (s, 1H), 4.49 (dd, 2H), 3.5-3.25 (m + m, 4H), 2.82 (s, 3H).

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Intermediate compound 37

1- (R) -phenyl-ethyl ester of acid 4- (3,5-bis-trifluoromethyl-benzyl-carbamoyl) -3- (4-fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid  (Diasteréomer 1) (37a) 1- (R) -phenyl-ethyl ester of acid 4- (3,5-bis-trifluoromethyl-benzyl-carbamoyl) -3- (4-fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid  (Diasteréomer 2) (37b)

To a solution of carbonyl-dimidazole (402 mg) in DCM (8.3 mL), at rt, in N 2, was added alcohol (R) -sec-phenylethyl (0.3 mL). The solution was stirred at rt for 1 h. The compound of Example 11 (790 mg) in acetonitrile anh. (8.3 mL) was then added to the solution and the reaction mixture was heated to 50 ° C without a water condenser to evaporate the DCM. A water condenser was then adjusted to the flask and the reaction mixture was refluxed for 4 h. The solvent was then evaporated and the residue was partitioned between AcOEt / 1N HCl. The phases were separated and the organic layer was washed with sat. NaCl. ac. (2x). It was then dried and the solvent was evaporated. The unpurified oil was purified by flash chromatography (CH / AcOEt 8: 2). The mixture of fractions were subjected to chromatography again using the same conditions. Intermediates 37a (242 mg) and 37b (152 mg) were obtained as white foams.

Intermediate 37a : NMR (DMSO) δ (ppm): 7.90 (s, 1H); 7.67 (s, 2H); 7.37-7.24 (m, 6H); 6.95 (dd, 1 H); 6.81 (m, 1 H); 5.75 (q, 1 H); 4.60-4.41 (dd, 2H); 4.52 (m, 1 H); 3.83-3.00 (m, 6H); 2.88 (s, 3 H); 2.33 (s, 3 H); 1.48 (d, 3 H).

Intermediate 37b : NMR (DMSO) δ (ppm): 7.90 (s, 1H); 7.67 (s, 2H); 7.4-7.27 (m, 6H); 6.95 (dd, 1 H); 6.80 (m, 1 H); 5.74 (q, 1 H); 4.60-4.40 (dd, 2H); 4.50 (m, 1 H); 3.79 (m, 3 H); 3.00 (m, 3 H); 2.87 (s, 3 H); 2.29 (s, 3 H); 1.46 (d, 3 H).

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Intermediate compound 38

1- (R) -phenyl-ethyl ester of acid 4 - {[1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-carbamoyl} -3- (S) - (4-fluoro-2-methyl-phenyl) -piperazine- 1-carboxylic (diastereoisomer 1) (38a) 1- (R) -phenyl-ethyl ester of acid 4 - {[1- (S) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-carbamoyl} -3- (R) - (4-fluoro-2-methyl-phenyl) -piperazine- 1-carboxylic (diastereoisomer 2) (38b)

To a solution of 1,1'-carbonyl diimidazole (0.163 g) in DCM (5 ml) was added (R) -sec-phenethyl alcohol (0.122 g) and the mixture was stirred at room temperature for 30 min. Then a solution of the compound of Example 2 (0.250 g) in acetonitrile (5 ml) was added and the mixture was refluxed for 4 h. The mixture was cooled and AcOEt was added. The organic phase was washed with 1 N HCl (2 x 50 mL) and with brine, dried and concentrated to give the crude mixture of diastereoisomers, which were separated by flash chromatography (with a mixture of CH and AcOEt 8: 2) to thereby obtain the title compound 38a (diastereoisomer 1 - 0.08 g) and the title compound 38b (diastereoisomer 2 - 0.08 g).

intermediate compound 38a : NMR (CDCl3) δ (ppm) 7.74 (s, 1H); 7.52 (s, 2H); 7.40-7.24 (m, 5H); 7.18 (m, 1 H); 6.87 (m, 1 H); 6.80 (m, 1 H); 5.86 (q, 1 H); 5.57 (q, 1 H); 4.7-4.46 (m, 1 H); 3.98 (m, 2H); 3.44-2.96 (m, 4H); 2.77 (s, 3 H); 2.36 (s, 3 H); 1.54 (m, 6H).

intermediate 38b : NMR (CDCl3) δ (ppm) 7.74 (s, 1H); 7.53 (s, 2H); 7.40-7.26 (m, 5H); 7.16 (m, 1 H); 6.87 (m, 1 H); 6.78 (m, 1 H); 5.86 (q, 1 H); 5.57 (m, 1 H); 4.62 (m, 1 H); 4.04 (m, 1 H); 3.84 (m, 1 H); 3.50-3.04 (m, 4H); 2.76 (s, 3 H); 2.41 (s, 3 H); 1.56 (m, 6H).

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Intermediate compound 39

(+) (S) -3- (4-Fluoro-2-methyl-phenyl) -piperazin-2-one

Method TO

To a suspension of intermediate 25 (35 g) in AcOEt (900 ml) was added L (+) - mandelic acid (27.3 g). The suspension was stirred at rt for 1 h and then at 3-5 ° C for 2 h, filtered and dried under vacuum at rt to obtain the crude L (+) - 3- (4-fluoro-2-methyl mandelate) -phenyl) -piperazin-2-one (37 g), which was suspended in AcOEt (370 ml) and heated to reflux until complete solubilization was obtained, and then cooled to room temperature and stirred for 2 hours Additional, filtered, washed with AcOEt (150 ml) and dried under vacuum, whereby L (+) - 3- (4-fluoro-2-methyl-phenyl) -5,6- mandelate was obtained pyrazin-2-one (30.4 g) as a white solid material. This material (30.4 g) was suspended in AcOEt (300 ml) and treated with NaOH (0.73 M, 155 ml) saturated with NaCl. Then the organic phase was washed with water (90 ml). The aqueous phase was extracted countercurrently 4 times with AcOEt (90 ml). The combined organic phase (1,800 ml) was dried over 10 g of Na2SO4 and concentrated under vacuum to obtain the title compound (25.04 g) as a white foam.

Method B

To a solution, heated to 45 ° C, of intermediate 25a (168 g) in ethyl acetate (2,000 ml) was added L (+) - mandelic acid (116 g) and 3,5-dichloro-salicylic-aldehyde (10 , 8 g). The solution was stirred for 30 min at 45 ° C and then seeded with white crystals of L (+) - 3- (4-fluoro-2-methyl-phenyl) -piperazin-2-one mandelate (0.4 g ). The suspension obtained was stirred under a nitrogen atmosphere at 45 ° C for 16 hours, and then stirred for a further 4 hours at 0 ° C, washed with cooled ethyl acetate (2 x 200 ml) and then dried under vacuum at room temperature for 2 hours to obtain the L (+) - 3- (4-fluoro-2-methyl-phenyl) -piperazin-2-one (126.22 g) mandelate as a white / yellowish solid material that was suspended in DCM (2,760 ml) and then 0.8 M NaOH in brine (17.35 g of NaOH in 530 ml of brine) was added. The organic phase was then washed with brine (380 ml) and the aqueous phase was extracted in countercurrent 4 times with DCM (4 x 1,500 ml). The combined organic phase was dried and concentrated to obtain the title compound (60.35 g).

1 H-NMR (DMSO) δ (ppm) 7.77 (broad m, 1H); 7.24 (dd, 1 H); 6.96 (dd, 1 H); 6.92 (td, 1 HOUR); 4.43 (s, 1 H); 3.30 (m, 1 H); 3.14 (m, 1 H); 2.92 (m, 1 H); 2.82 (m, 2H); 2.33 (s, 3 H).

HPLC (high liquid phase chromatography yield): Chiralcel OJ (4.6 x 250 mm) of Daicel; Mobile phase: mixture of n-hexane and ethanol 80:20 v / v; Flow rate: 1 ml / min; Detector: UV @ 265 nm (or 210 nm for higher signals); Dissolution phase: mixture of n-hexane and ethanol 80:20 v / v; Sample concentration 1 mg / ml; 5 injection \ mul; Retention times 2: 8.4 min; [α] D (solvent CHCl 3, Source: Na: Cell volume [ml]: 1; Path length in cell [dm]: 1; Cell temperature [° C]: 20; Wavelength [nm]: 589; Sample Concentration [% w / v]: 1.17] = +17.9.

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Intermediate compound 40

[1- (R) - (3,5-Bis-trifluoromethyl-phenyl-ethyl) -methyl-amide of acid 2- (S) -4-Fluoro-2-methyl-phenyl-3-oxo-piperazine-1-carboxylic  (40a)

Y

[1- (S) - (3,5-Bis-trifluoromethyl-phenyl-ethyl) -methyl-amide of acid 2- (S) -4-Fluoro-2-methyl-phenyl-3-oxo-piperazine-1-carboxylic  (40b)

To a solution of intermediate 39 (12.1 g) in anhydrous DCM (270 ml) was added TEA (16.4 ml). The solution was cooled to 0 ° C and a solution of triphosgene (7.3 g) in anhydrous DCM (60 ml) was added dropwise over 40 min. The reaction mixture was stirred at 0 ° C for 4 h and brought back to rt. DIPEA (20.2 ml) was then added, followed by a solution of [1- (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-amine (23.6 g) in acetonitrile (300 ml) and an additional amount of acetonitrile (300 ml). The reaction mixture was heated to 95 ° C (oil bath at T ° C) without any water condenser to evaporate the DCM. When the internal temperature had reached 70 ° C, the flask was equipped with a water condenser and the reaction mixture was heated at 70 ° C for an additional 2 h (for a total of 4 h). Then it was brought to rt and the solvent evaporated. The residue was partitioned between DCM and 2% HCl and the phases separated. The aqueous layer was extracted with DCM (1 x) and the combined organic extracts dried. The solid materials were filtered and the solvent was evaporated to give a crude mixture of title compounds that were purified by flash chromatography (mixture of AcOEt and CH 8: 2) to obtain the title compounds 40a (8.8 g) and 40b (9.0 g) as white foams.

intermediate 40a : NMR (1 H, DMSO-d 6): δ 8.16 (s, 1H); 7.98 (s, 2 H); 7.19 (dd, 1 H); 6.97 (dd, 1 H); 6.87 (td, 1 H); 5.34 (s, 1 H); 5.14 (q, 1 H); 3.45-3.2 (m, 4H); 2.53 (s, 3 H); 2.27 (s, 3 H); 1.56 (d, 3 H).

intermediate 40b : NMR (1 H, DMSO-d 6): δ 8.16 (s, 1H); 7.95 (s, 2 H); 7.19 (dd, 1 H); 6.98 (dd, 1 H); 6.90 (td, 1 H); 5.29 (q, 1 H); 5.28 (s, 1 H); 3.45-3.15 (m, 4H); 2.66 (s, 3 H); 2.27 (s, 3 H); 1.52 (d, 3 H).

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Intermediate compound 41

(3,5-bis-Trifluoromethyl-benzyl) -methyl-amide of the acid 4- [2- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -ethyl] -2- (4-fluoro-2- methyl-phenyl) -piperazine-1-carboxylic acid

To a solution of example 8 (0.05 g) in anhydrous DMF (1 mL), in N2, at room temperature, TEA (40 µl) and N- (2-bromoethyl) phthalimide (28) were added mg) The reaction mixture was stirred at 80 ° C for 5 h and then cooled to room temperature. It was poured into NaCl ac. sat. and the phases were separated. The organic layer was washed with sat. NaCl. ac. (2x), was dried and the solvent was evaporated. The unpurified product was purified by flash chromatography (CH / AcOEt 1: 1) to give the title compound (0.25 g) as a yellow oil.

NMR (DMSO) δ (ppm) 7.94 (s, 1H), 7.80-7.90 (m, 4H), 7.67 (s, 2H), 7.33 (m, 1H), 6.91 (dd, 1H), 6.45 (td, 1H), 4.60 (d, 1H), 4.34 (m, 2H), 3.80 (m, 1H), 3.64 (m, 1H), 3.18 (m, 1H), 2.82 (s, 3H), 2.79 (m, 1H), 2.80 (m, 1H), 2.66 (m, 1H), 2.60 (m, 2H), 2.46 (m, 1H), 2.26 (m, 1H), 2.27 (s, 3H).

IR (Nujol) (cm -1) 1650-1773.

MS ( m / z ) 651 [MH], 673 [M + Na] +.

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Intermediate compound 42

1- (4-Fluoro-2-methyl-phenyl) -propane-1,2-dione

1) To a suspension of magnesium chips (283 mg) in THF anh. (3 mL), at t.a., in N2, a small was added crystal of I 2, followed by 10% of a solution of 1-Bromo-4-fluoro-2-methyl-benzene (2.0 g) in anhydrous THF (8 mL). The suspension was heated gently (hot air gun) until the Brown color. The remaining bromide was added dropwise, keeping the reaction mixture warm (50-60 ° C)  With an oil bath. After the addition was complete (15 min) the suspension was stirred at 70 ° C until the chips were magnesium had reacted almost completely (2 h). The new one Brown solution was used in the next stage.

2) A solution of LiBr (2.26 g) in THF anh. (26 mL) was added dropwise to a suspension of CuBr (1.82 g) in THF anh. (26 mL). The reaction mixture was stirred at rt for 1 h. The reaction mixture was then brought to -78 ° C and the Grignard reagent prepared above was added dropwise followed by pyruvilium chloride (1.13 g). The reaction mixture was stirred at -78 ° C for 2 h. THF was evaporated and the residue was placed in AcOEt. The organic layer was washed with NH4Cl aq. sat. (2x), dried and evaporated to an unpurified oil, which was purified by flash chromatography (CH / AcOEt 95: 5) to give the title compound as a yellow oil (0.58 g). NMR (CDCl3) δ (ppm) 7.68 (m, 1H), 6.98 (m, 2H), 2.56-2.52 (2s, 6H).

IR (film) (cm -1) 1712, 1674.

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Intermediate compound 43

5- (4-Fluoro-2-methyl-phenyl) -6-methyl-2,3-dihydro-pyrazine

To a solution of intermediate 42 (0.58 g) and ethylenediamine (0.22 mL) in toluene (13 mL), at rt, in N 2, Na 2 SO 4 anh was added. (2 g). The reaction mixture was heated at reflux for 6 h. It was then cooled to rt and filtered. The solids were rinsed with DCM. The solvent was evaporated and the unpurified oil was purified by flash chromatography (AcOEt) to give the title compound as an orange oil (0.44 g).

NMR (CDCl3) δ (ppm) 7.18 (m, 1H), 7.0-6.9 (m, 2H), 3.6-3.45 (2m, 4H), 2.20 (s, 3H), 1.88 (t, 3H).

IR (Film) (cm -1) 1612, 1530.

MS ( m / z ) 204 [M] +.

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Intermediate compound 44

Acid benzyl ester 2-methyl-3- (2-methyl-4-fluoro) -phenyl-piperazine-1-carboxylic acid

To a solution of intermediate 43 (554 mg) in MeOH anh. (11 mL), in N2, at rt, 10% Pd / C (110 mg) was added and the reaction mixture was placed under an H2 atmosphere for 2 h. The catalyst was then filtered (filter paper) and rinsed with AcOEt. The solvent was evaporated and the residue was dried under vacuum. 2- (4-Fluoro-2-methyl-phenyl) -3-methyl-piperazine was obtained as a yellow oil (565 mg) and was dissolved in DCM anh. (27 mL), at -5 ° C, in N2. TEA (549 µL) and benzyloxycarbonyl chloride (426 µL) were added to this solution. The solution was stirred at -5 ° C for 2 h, then poured into aq NaHCO3 / DCM. sat. and the phases were separated. The aqueous layer was extracted with DCM (1x) and the combined organic extracts were dried. The solids were filtered and the solvent was evaporated. The unpurified oil was purified by flash chromatography (CH / AcOEt 1: 1) to give the title compound obtained as a yellow oil (111 mg).

NMR (CDCl3) δ (ppm) 7.45-7.36 (m, 6H), 6.86 (m, 2H), 5.17 (m, 2H), 4.48-4.36 (m, 1H), 4.09-4.04 (2d, 1H), 4.05-3.94 (2bd, 1H), 3.25-2.88 (m, 3H), 2.40 + 2.28 (2s, 3H), 0.97 + 0.96 (2d, 3H).

IR (Film) (cm -1) 1688.

MS ( m / z ) 343 [MH] +.

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Intermediate compound Four. Five

Acid benzyl ester 4 - [(3,5-bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -3- (4-fluoro-2-methyl-phenyl) -2-methyl-piperazine-1-carboxylic acid

To a solution of intermediate 44 (358 mg) in DCM anh. (15 mL), at 0 ° C, in N2, TEA (292 µL). To this solution was added a triphosgene solution (140 mg) in DCM anh. (6 mL). The reaction mixture was stirred at 0 ° C. for 2 h.

To this solution were added DIPEA (181 µL) and N-methyl-bis (trifluoromethyl) benzylamine hydrochloride (370 mg). The solution was stirred at rt for 18 h. It was then diluted with DCM, washed with 10% citric acid (1x) and dried. The solvent was evaporated and the unpurified oil was purified by flash chromatography (CH / AcOEt 6: 4) to give the title compound (545 mg) as a white foam.

NMR (CDCl3) δ (ppm) 7.76 (s, 1H). 7.50 (s, 2H), 7.34-7.30 (m, 5H), 7.00 (m, 1H), 6.85 (m, 1H), 6.76 (m, 1H), 5.2-5.1 (dd, 2H), 4.75 (d, 1H), 4.30 (d, 1H), 4.65 (m, 1H), 4.35 (m, 1H), 4.00 (m, 1H), 3.54-3.40 (m, 2H), 3.1 (m, 1H), 3.06 (s, 3H), 2.38 (s, 3H), 1.05 (d, 3H).

IR (Film) (cm -1) 3437, 1705, 1664.

MS ( m / z ) 626 [MH] +.

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Intermediate compound 46

3- (2-Methyl-4-fluoro-phenyl) -5-methyl-5,6-dihydro-1H-pyrazin-2-one

Under an inert atmosphere, intermediate 23 (0.2 g) was dissolved in dry toluene (5 mL), then 1,2-diaminopropane (0.102 mL) was added dropwise followed by Na2SO4 ( 0.2 g) and the reaction mixture was refluxed for 2 h; The solids were filtered and the unpurified product obtained after evaporation of the solvent was purified by flash chromatography (AcOEt) to provide the title compound in a mixture with 3- (2-methyl4-fluoro-phenyl) -6-methyl-5 , 6-dihydro-1 H -pyrazin-2-one (0.200 g).

1 H-NMR (DMSO) δ (ppm) 8.42 (broad s, 1H), 7.24 (m, 1H), 7.02 (m, 2H), 3.85 (m, 1H), 3.40 (dt, 1H), 3.1-3 (t, 1H), 2.18 (s, 3H), 1.25 (d, 3H).

IR (Nujol) (cm -1) 3450, 1682, 1614.

MS ( m / z ) 221 [MH] +.

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Intermediate compound 47

3- (2-Methyl-4-fluoro-phenyl) -5-methyl-piperazin-2-one (mixture of syn enantiomers)

Intermediate 46 (0.188 g) was dissolved in MeOH (4 mL) and 10% Pd / C (36 mg) was added. After 2 h the reduction was complete. The reaction mixture was filtered on a celite pad, the solvent was removed under reduced pressure and the unpurified product was purified by flash chromatography (AcOEt / MeOH 9: 1) to provide a 9: 1 mixture of the title compound and the anti -enantiomers (0,110 g).

1 H-NMR (DMSO) δ (ppm) 7.88 (s, 1H), 7.07-6.92 (m, 3H), 4.48 (s, 1H), 3.3 (m, 1H), 2.91 (m, 2H), 2.65 (wide s, 1H), 2.34 (s, 3H), 0.95 (d, 3H).

IR (Nujol) (cm -1) 3441, 3285, 1675.

MS ( m / z ): 223 [MH] +.

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Intermediate compound 48

(3,5-bis-Trifluoromethyl-benzyl) -methyl-amide of the acid 2- (2-methyl4-fluoro-phenyl) -3-oxo-piperazine-6-methyl-1-carboxylic acid;  syn enantiomer mixture

To a solution of intermediate 47 (0.105 g) and triethylamine (0.197 mL) in dry DCM (5 mL) was added dropwise, at 0 ° C, a solution of triphosgene (0.056 g) in dry DCM (3 mL) under a inert atmosphere The temperature was maintained at 0 ° C for 3 h, before the addition of DIPEA (0.3 mL) followed by 3,5-bistrifluoromethyl methyl amine hydrochloride (0.166 g). The reaction mixture was stirred at room temperature overnight before being diluted with DCM and washed with a 1N solution of HCl, H2O and brine in sequence. The organic phase was dried and the unpurified product obtained after evaporation of the solvent was purified by flash chromatography (AcOEt / MeOH 9: 1) to give the title compound as a foam (0.085 g).

1 H NMR (DMSO) δ (ppm) 8.08 (broad t, 1H), 7.95 (s, 1H), 7.63 (s, 2H), 7.13 (t, 1H), 6.87 (d, 1H), 6.79 (t, 1H), 5.21 (s, 1H), 4.51 (dd, 2H), 3.64 (m, 1H), 3.30 (m, 1H), 3.18 (m, 1H), 2.77 (s, 3H), 2.25 (s, 3H), 1.20 (d, 3H).

IR (Nujol) (cm -1) 1675.

MS ( m / z ): 506 [MH] +.

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Intermediate compound 49

Acid methyl ester 2- (3,5-bis-trifluoromethyl-phenyl) -acrylic

Tetrakis (triphenylphosphine) of palladium (331 g), copper iodide (0.414 g) and methyl ester of 2-tributylstanyl-2-propeneic acid (2.82 g) were added to a solution of 3,5- (bis- trifluoromethyl) iodobenzene (1 g) in dry DMF (10 mL) under a nitrogen atmosphere. The solution was stirred at rt for 16 h, then diluted with water and extracted with AcOEt. The organic extract was dried, concentrated in vacuo and purified by flash chromatography (CH / AcOEt 9: 1) to give the title compound (180 mg).

IR (CDCl 3): 1727 (C-O) cm -1.

NMR (DMSO) δ (ppm) 7.95 (s, 1H); 7.89 (s, 1 HOUR); 7.87 (s, 1 H); 6.6 (s, 1 H); 6.06 (s, 1 H); 3.87 (s, 3 H).

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Intermediate compound fifty

Acid methyl ester 1- (3,5-bis-trifluoromethyl-phenyl) -cyclopropanecarboxylic acid

Sodium hydride (60% suspension in mineral oil-86 mg) was added to a suspension of trimethylsulfoxonium iodide (515 mg) in dry DMF under a nitrogen atmosphere. The suspension was stirred at rt for 15 min., Then a solution of intermediate 49 (0.58 g) in dry DMF (6 mL) was added. The mixture was stirred at rt for 30 min., Then diluted with brine and extracted with ethyl acetate. The organic extract was dried, concentrated in vacuo and purified by flash chromatography (CH / AcOEt 9: 1) to give the title compound (90 mg) as a colorless oil.

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Intermediate compound 51

Acid 1- (3,5-bis-trifluoromethyl-phenyl) -cyclopropanecarboxylic acid

A mixture of intermediate 50 (90 mg) and lithium hydroxide (55.4 mg) in methanol (10 mL) was heated at reflux for 2 h. The organic extract was concentrated in vacuo and was partitioned between a solution of saturated ammonium chloride and AcOEt. The organic layer was washed with brine, dried and concentrated in vacuo to give the title compound (80 mg) as a colorless oil.

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Intermediate compound 52

4 [1- (3,5-Bis-Trifluoromethyl-phenyl) cyclopropylcarbamoyl] -3- (S) - (4-fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid tert -butyl ester

TEA (150 µL) and diphenylphosphorylazide (175 µL) were added to a solution of intermediate 51 (80 mg) in dry toluene (25 mL) previously cooled to 0 ° C under a nitrogen atmosphere. The solution was stirred at rt for 3 h, then intermediate 54 (88 mg) was added and the mixture was heated at 100 ° C for 1 h. The mixture was allowed to cool to rt and was partitioned between water and AcOEt. The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH / AcOEt 6: 4) to give the title compound as a colorless oil (90 mg).

NMR (DMSO) δ (ppm) 7.75 (broad s, 1H), 7.67 (wide s, 2H), 7.29 (wide s, 1H), 7.18 (dd, 1H), 6.96 (dd, 1H), 6.86 (dt, 1H); 5.17 (t, 1H), 3.75-3.42 (m, 5H), 3.18 (m, 1H), 2.29 (s, 3H), 1.3 (s, 9H); 1.3-1.1 (m, 4H).

MS: m / z = 590 [M + H] +.

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Intermediate compound 53

4 - {[1- (3,5-Bis-Trifluoromethyl-phenyl) -cyclopropyl] -methyl-carbamoyl} -3- (S) - (4-fluoro-2-methyl-phenyl) tert -butyl ester -piperazine-1-carboxylic

Sodium tert-butoxide (38.5 mg) was added to a solution of intermediate 52 (80 mg) in dry THF. The solution was stirred at rt for 10 min., Then methyl iodide (40 µL) was added and stirring was continued for 1 h. The mixture was divided between water and AcOEt. The organic layer was dried, concentrated in vacuo to give the title compound as a colorless oil (90 mg).

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NMR (DMSO) δ (ppm) 7.8 (broad s, 1H), 7.38 (dd, 1H), 7.34 (broad s, 2H), 6.97 (dd, 1H), 6.93 (dt, 1H); 4.5 (m wide, 1H), 3.64-2.97 (m, 9H), 2.28 (s, 3H), 1.38 (broad s, 9H); 1.36-1.24 (2m, 4H).

MS: m / z = 604 [M + H] +, 626 [M + Na] +.

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Intermediate compound 54

1- (tert-Butoxycarbonyl) -3- (S) - (4-fluoro-2-methyl-phenyl) -piperazine

Di-tert-butyldicarbonate (271 mg) was added to a solution of intermediate 81 (301 mg) and TEA (315 µL) in DCM (10 mL) previously cooled to 0 ° C under a nitrogen atmosphere. The solution was stirred at 0 ° C for 40 min., Then it was concentrated in vacuo . The residue was divided between water and AcOEt. The organic layer was washed with brine, dried and concentrated in vacuo . The residue was purified by flash chromatography (CH / AcOEt 6: 4) to give the title compound (80 mg) as a colorless gum.

NMR (d_ {6} -DMSO): δ (ppm) 7.52 (m, 1 H); 7.07-6.98 (m, 2H); 3.94-3.74 (m, 3H); 3.0-2.5 (m, 4H); 2.33 (s, 3 H); 1.4 (s, 9H).

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Intermediate compound 55

3- (3,5-bis-Trifluoromethyl-benzoyl) -1-vinyl-pyrrolidin-2-one

Trimethylsilyldiazomethane (11.5 mL) was added dropwise to a solution of 3,5-bis- (trifluoromethyl) benzoic acid (2 g) in dry toluene (20 mL) and methanol (0.5 mL) previously cooled to 0 ° C under an atmosphere of nitrogen. The solution was stirred at rt for 1 h, then concentrated in vacuo to give the 3,5-bis- (trifluoromethyl) -benzoic acid methyl ester (2 g) as a colorless oil. A solution of the 3,5-bis- (trifluoromethyl) -benzoic acid methyl ester (2 g) and 1-vinyl-2-pyrrolidinone (863 µL) was added to a mixture of sodium hydride (60% suspension in mineral oil-0.41 g) in dry toluene (30 mL) previously heated to reflux. The mixture was stirred for 12 h, then was partitioned between a solution of saturated ammonium chloride and AcOEt. The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH / AcOEt 8: 2) to give the title compound (1.6 g) as a beige oil.

MS: m / z = 352 [M + H] +.

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Intermediate compound 56

5- (3,5-bis-Trifluoromethyl-phenyl) -3,4-dihydro-2H-pyrrole

A solution of intermediate 55 (1.6 g) in THF (30 mL) was added dropwise in 1.5 h to a boiling solution of 6N HCl (50 mL) while distilling the THF. At the end of the addition, the distillation apparatus was removed and reflux was continued for more than 4 h. The mixture was cooled to 0 ° C and a 30% KOH solution was added until a pH = 12 was reached. The compound was extracted with DCM (4x10 mL). The combined organic extracts were dried, concentrated in vacuo and the residue was purified by flash chromatography (CH / AcOEt 7: 3) to give the title compound (100 mg) as a stick yellow oil.

NMR (DMSO) δ (ppm) 8.38 (s, 2H); 8.22 (s, 1 HOUR); 4.0 (t, 2H), 3.03 (tt, 2H); 1.99 (m, 2H).

MS: m / z = 282 [M + H] +.

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Intermediate compound 57

2- (3,5-bis-Trifluoromethyl-phenyl) -pyrrolidine

Sodium borohydride (1.5 eq) was added to a solution of intermediate compound 56 (100 mg) in methanol (5 mL) previously cooled to 0 ° C under a nitrogen atmosphere. The solution was diluted with water and extracted with AcOEt. The organic extract was dried and concentrated in vacuo to give the title compound (103 mg) as a yellow stick oil.

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Intermediate compound 58

4- [2- (3,5-Bis-Trifluoromethyl-phenyl) -pyrrolidin-1-carbonyl] -3- (S) - (4-fluoro-2-methyl-phenyl) -piperazine tert - butyl ester -1-carboxylic (58 to Enantiomer A) Acid tert-butyl ester 4- [2- (3,5-Bis-Trifluoromethyl-phenyl) -pyrrolidin-1-carbonyl] -3- (S) - (4-fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid  (58 b Enantiomer B)

A solution of triphosgene (47 mg) in DCM (2 mL) was added dropwise to a solution of intermediate 54 (103 mg) and TEA (97 µL) in acetonitrile (3 mL) previously cooled to 1 ° C under an atmosphere of nitrogen The solution was stirred at rt for 2 h, then intermediate 56 (103 mg) was added and the solution was heated at reflux for 5 h. After cooling to rt, the solution was diluted with water and extracted with AcOEt. The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH / AcOEt from 8: 2 to 7: 3) to give the title compound 58a (15 mg) and the title compound 58b (20 mg)

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Intermediate compound 59

Acid 2- (3,5-bis-trifluoromethyl-phenyl) -pent-4-enoic

Butyl lithium (1.6 M in hexane-1.7 mL) was added to a solution of diisopropylamine (4.88 g) in dry THF (40 mL) previously cooled to -78 ° C under a nitrogen atmosphere. The solution was allowed to warm to 0 ° C and was stirred at this temperature for 1 h. Then, the solution was cooled to 78 ° C and a solution of 3,5- (bis-trifluoromethyl) phenylacetic acid (3 g) in THF (10 mL) was added. The solution was allowed to warm to 0 ° C and was stirred at this temperature for 2 h. The solution was cooled again to -78 ° C and 2-propenyl iodide (1.2 mL) was added. The solution was allowed to warm to rt and was stirred at rt for 3 h. The solution was quenched with 5N HCl to a pH = 2 and extracted with AcOEt. The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH / AcOEt 75:25) to give the title compound (2.4 g) as a yellow oil.

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Intermediate compound 60

Acid tert-butyl ester 4- [1- (3,5-Bis-Trifluoromethyl-phenyl) -but-3-enylcarbamoyl] -3- (S) - (4-fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid  (60th Enantiomer A) Acid tert-butyl ester 4- [1- (3,5-Bis-Trifluoromethyl-phenyl) -but-3-enylcarbamoyl] -3- (S) - (4-fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid  (60b Enantiomer B)

TEA (885 µL) and diphenylphosphorylazide (1.3 g) were added to a solution of intermediate 59 (500 mg) in dry toluene (25 mL) previously cooled to 0 ° C under a nitrogen atmosphere. The solution was stirred at rt for 3 h, then the compound of intermediate 54 (521 mg) was added and the mixture was heated at 100 ° C for 1 h. The mixture was allowed to cool to rt and was partitioned between water and AcOEt. The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH / AcOEt from 8: 2 to 7: 3) to give the title compound 60a (480 mg) and the title compound 60b (450 mg) as white foams.

Intermediate 60a : NMR (DMSO) δ (ppm) 7.94 (s, 2H); 7.84 (s, 1 H); 7.14 (t, 1 H); 6.94 (dd, 1H), 6.84 (dt, 1H); 6.66 (d, 1 H); 5.62 (m, 1 H); 5.18 (t, 1 H); 5.0-4.9 (m, 2H), 4.84 (m, 1H); 3.82 (dt, 1 H); 3.75 (m, 1 H); 3.65 (broad d, 1H); 3.43 (broad t, 1H); 3.52 (dd, 1 H); 3.17 (m, 1 H); 2.45 (t, 2H), 2.24 (s, 3H); 1.29 (m, 1 H).

Intermediate 60b : NMR (DMSO) δ (ppm) 7.84 (s, 2H); 7.81 (s, 1 H); 7.14 (t, 1 H); 6.97 (dd, 1H), 6.86 (dt, 1H); 6.53 (broad d, 1H); 5.66 (m, 1 H); 5.15 (t, 1 H); 5.05-4.9 (m, 3H), 3.89 (dt, 1H); 3.75-3.65 (b, 1H); 3.63 (broad d, 1H); 3.52 (dd, 1 H); 3.43 (dt, 1 H); 3.2 (m, 1 H); 2.5 (t, 2H), 2.3 (s, 3H); 1.28 (m, 1 H).

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Intermediate compound 61

4- {2-Propenyl- [1- (3,5-bis-trifluoromethyl-phenyl) -but-3-enyl] -1-carbamoyl} -3- (S) - (4- tert -butyl ester fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid (enantiomer A)

Sodium tert-butoxide (245 mg) was added to a solution of intermediate 60a (480 mg) in dry THF (20 mL). The solution was stirred at rt for 10 min., Then 2-propenyl iodide (400 µL) was added and stirring was continued for 3 h. The mixture was divided between water and AcOEt. The organic layer was dried and concentrated in vacuo to give the title compound as a colorless oil (540 mg).

NMR (DMSO) δ (ppm) 7.94 (s. 1H); 7.79 (s, 2H); 7.28 (dd, 1 H); 6.98 (dd, 1H), 6.84 (dt, 1H); 5.63 (m, 1 H); 5.46 (m, 1 H); 5.18 (t, 1 H); 5.14-4.9 (m, 4H), 4.4 (d width, 1H); 3.98 (dd, 1 H); 3.86 (dd, 1 H); 3.7-3.55 (m, 2H); 3.4-2.7 (m, 4H); 2.32 (s, 3H), 1.36 (s, 9H).

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Intermediate compound 62

4- [2- (3,5-Bis-Trifluoromethyl-phenyl) -3,6-dihydro-2 H -pyridine-1-carbonyl] -3- (S) - (4-fluoro acid tert-butyl ester -2-methyl-phenyl) -piperazine-1-carboxylic acid (enantiomer A)

Benzylidene-bis (tricyclohexylphosphine) dichlororuthenium (34 mg) was added to a solution of intermediate 61 (540 mg) in dry DCM (20 mL) under a nitrogen atmosphere. The solution was stirred at rt for 4 h, then diluted with a saturated ammonium chloride solution and extracted with AcOEt. The organic layer was dried, concentrated in vacuo and was the residue was purified by flash chromatography (CH / AcOEt 75:25) to give the title compound (0.35 g) as a brown oil.

NMR (DMSO) δ (ppm) 7.87 (s, 1H); 7.74 (s, 2H); 7.29 (dd, 1 H); 6.93 (dd, 1H), 6.81 (dt, 1H); 5.8-5.6 (m, 2H); 5.2-4.9 (m, 4H); 4.7 (t, 1 H); 4.46 (broad s, 1H); 4.0-2.73 (m, 10H); 2.31 (s, 3H), 1.38 (s, 9H).

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Intermediate compound 63

1- (tert-Butoxycarbonyl) -3- (4-fluoro-2-methyl-phenyl) -piperazine

Di- tert- butyldicarbonate (271 mg) was added to a solution of intermediate 7 (301 mg) and TEA (315 µL) in DCM (10 mL) previously cooled to 0 ° C under a nitrogen atmosphere. The solution was stirred at 0 ° C for 40 min., Then it was concentrated in vacuo . The residue was divided between water and AcOEt. The organic layer was washed with brine, dried and concentrated in vacuo . The residue was purified by flash chromatography (CH / AcOEt 6: 4) to give the title compound (80 mg) as a colorless gum.

NMR (d_ {6} -DMSO): δ (ppm) 7.52 (m, 1 H); 7.07-6.98 (m, 2H); 3.94-3.74 (m, 3H); 3.0-2.5 (m, 4H); 2.33 (s, 3 H); 1.4 (s, 9H).

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Intermediate compound 64

4 - {[1- (3,5-Bis-Trifluoromethyl-phenyl) -but-3-enyl] -carbamoyl} -3- (4-fluoro-2-methyl-phenyl) -piperazine tert - butyl ester -1-carboxylic (64th Diastereoisomer A) Tert - butyl ester 4- [1- (3,5-bis-trifluoromethylphenyl) -but-3-enilcarbamoil] -3- (4-fluoro-2-methyl-phenyl) -piperazine-1-carboxylic (64b Diastereoisomer B)

TEA (700 µL) and diphenylphosphorylazide (812 µL) were added to a solution of intermediate 59 (400 mg) in dry toluene (20 mL) previously cooled to 0 ° C under a nitrogen atmosphere. The solution was stirred at rt for 3 h, then 400 mg of intermediate 63 was added and the mixture was heated at 100 ° C for 1 h. The mixture was allowed to cool to rt and was partitioned between water and AcOEt. The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH / AcOEt 8: 2) to give the title compound 64a (340 mg) and the title compound 64b (250 mg).

Intermediate 64a NMR (DMSO) δ (ppm) 7.94 (s, 2H); 7.84 (s, 1 H); 7.14 (t, 1 H); 6.94 (dd, 1H), 6.84 (dt, 1H); 6.66 (d, 1 H); 5.62 (m, 1 H); 5.18 (t, 1 H); 5.0-4.9 (m, 2H), 4.84 (m, 1H); 3.82 (dt, 1 H); 3.75 (m, 1 H); 3.65 (broad d, 1H); 3.43 (broad t, 1H); 3.52 (dd, 1 H); 3.17 (m, 1 H); 2.45 (t, 2H), 2.24 (s, 3H); 1.29 (m, 1 H).

Intermediate 64b NMR (DMSO) δ (ppm) 7.84 (s, 2H); 7.81 (s, 1 H); 7.14 (t, 1 H); 6.97 (dd, 1H), 6.86 (dt, 1H); 6.53 (broad d, 1H); 5.66 (m, 1 H); 5.15 (t, 1 H); 5.05-4.9 (m, 3H), 3.89 (dt, 1H); 3.75-3.65 (b, 1H); 3.63 (broad d, 1H); 3.52 (dd, 1 H); 3.43 (dt, 1 H); 3.2 (m, 1 H); 2.5 (t, 2H), 2.3 (s, 3H); 1.28 (m, 1 H).

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Intermediate compound 65

4 - {[1- (3,5-Bis-Trifluoromethyl-phenyl) -but-3-enyl] -methyl-carbamoyl} -3- (4-fluoro-2-methyl-phenyl) tert -butyl ester -piperazine-1-carboxylic acid (Diastereoisomer A)

Sodium tert -butoxide (28 mg) was added to a solution of intermediate 64a (70 mg) in dry THF (10 mL). The solution was stirred at rt for 30 min., Then methyl iodide (37 µL) was added. The reaction was stopped, so more sodium tert-butoxide (28 mg) and methyl iodide (37 µL) were added (2x) and stirring was continued for 18 h. The mixture was divided between water and AcOEt. The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH / AcOEt 8: 2) to give the title compound as a colorless oil (44 mg).

NMR (DMSO) δ (ppm) 7.91 (broad s, 1H); 7.68 (broad s, 2H); 7.22 (dd, 1 H); 6.94 (dd, 1H), 6.78 (dt, 1H); 5.72 (m, 1 H); 5.34 (dd, 1 H); 5.2-5.06 (2m, 2H), 4.41 (dd, 1H); 3.69 (m, 1 H); 3.3-2.75 (m, 9H); 2.32 (s, 3H), 1.4 (s, 9H).

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Intermediate compound 66

4- {methyl- [1- (3,5-bis-trifluoromethyl-phenyl) -but-3-enyl] -carbamoyl} -3- (4-fluoro-2-methyl-phenyl) tert -butyl ester -piperazine-1-carboxylic acid (diastereoisomer B)

Sodium tert -butoxide (28 mg) was added to a solution of intermediate 64b (70 mg) in dry THF (10 mL). The solution was stirred at rt for 30 min., Then methyl iodide (37 µL) was added. The reaction was stopped, so more sodium tert -butoxide (28 mg) and methyl iodide (37 µL) were added (2x) and stirring was continued for 18 h. The mixture was divided between water and AcOEt. The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH / AcOEt 8: 2) to give the title compound as a colorless oil (44 mg).

NMR (DMSO) δ (ppm) 7.91 (broad s, 1H), 7.81 (broad s, 2H); 7.25 (m, 1 H); 6.94 (m, 1H), 6.84 (m, 1H); 5.62 (m, 1 H); 5.14-4.94 (m, 2H); 5.11 (t, 1 H); 4.46 (m, 1 HOUR); 3.7 (dd, 2H); 3.65-3.32 (m, 2H); 3.3 (m, 1 H); 3.0 (m, 1 H); 2.76 (m, 2H); 2.76 (s, 3H), 2.31 (s, 3H); 1.39 (s, 9H).

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Intermediate compound 67

4- {2-Propenyl- [1- (3,5-bis-trifluoromethyl-phenyl) -but-3-enyl] -carbamoyl} -3- (4-fluoro-2-methyl-) tert -butyl ester phenyl) -piperazine-1-carboxylic acid (diastereoisomer A)

Sodium tert -butoxide (113 mg) was added to a solution of intermediate 64 to (220 mg) in dry THF (15 mL). The solution was stirred at rt for 10 min., Then 2-propenyl iodide (186 µL) was added and stirring was continued for 3 h. The mixture was divided between water and AcOEt. The organic layer was dried and concentrated in vacuo to give the title compound as a colorless oil (180 mg).

NMR (DMSO) δ (ppm) 7.94 (s, 1H); 7.78 (s, 2H); 7.27 (dd, 1 H); 6.97 (dd, 1H), 6.84 (dt, 1H); 5.62 (m, 1 H); 5.45 (m, 1 H); 5.17 (t, 1 H); 5.08 (d, 1 H); 5.04 (d, 1 H); 4.99 (d, 1H), 4.93 (d, 1H); 4.38 (m, 1 H); 3.95 (m, 1 H); 3.85 (dd, 1 H); 3.61 (m, 2H); 3.34 (m, 2 H); 3.08 (m, 2 H); 2.66 (m, 2 H); 2.31 (s, 3 H). 1.35 (s, 9H).

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Intermediate compound 68

4- [2- (3,5-Bis-Trifluoromethyl-phenyl) -3,6-dihydro-2 H -pyridine-1-carbonyl] -3- (4-fluoro-2-methyl) tert-butyl ester -phenyl) -piperazine-1-carboxylic acid (diastereoisomer A)

Benzylidene-bis (tricyclohexylphosphine) dichlororutenium (5 mol% 7.7 mg) was added to a solution of intermediate 67 (120 mg) in dry DCM (5 mL) under a nitrogen atmosphere. The solution was stirred at rt for 4 h, then diluted with a saturated ammonium chloride solution and extracted with AcOEt. The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH / AcOEt 7: 3) to give the title compound (85 g) as a brown oil.

NMR (DMSO) δ (ppm) 7.9 (s, 1H); 7.69 (s, 2H); 7.26 (dd, 1 H); 6.95 (dd, 1H), 6.82 (dt, 1H); 5.89 (m, 1 H); 5.68 (broad d, 1H); 5.28 (d, 1 H); 4.49 (dd, 4H); 4.2 (d, 1 H); 3.69 (dd, 1H); 3.64 (m, 1 H); 3.32 (m, 2 H); 3.31 (m, 1 H); 3.1 (m, 1 H); 2.7 (broad d, 1H); 2.53 (m, 1 H); 2.3 (s, 3H), 1.37 (s, 9H).

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Intermediate compound 69

Acid methyl ester 2- (3,5-bis-trifluoromethyl-phenyl) -2-methyl-propionic

(Trimethylsilyl) diazomethane (2M in hexane-3.68 mL) was added dropwise to a solution of (3,5-bis-trifluoromethyl-phenyl) -acetic acid (500 mg) and dry methanol (82 µL) in dry toluene (8 mL) at 0 ° C, under a nitrogen atmosphere. The reaction mixture was stirred at 0 ° C for 5 minutes, then the solvent was evaporated in vacuo to obtain the methyl ester of (3,5-bis-trifluoromethyl-phenyl) -acetic acid, a yellow stick oil (440 mg). This material was dissolved in dry THF (4.5 mL) at 0 ° C, under a nitrogen atmosphere and sodium bis (trimethylsilyl) -amide (1.0M in THF-4 mL) was added dropwise. After ten minutes, methyl iodide (958 µL) was added and the reaction mixture was stirred at rt for 2 hours. The reaction was quenched with a 2N hydrochloric acid solution (7 mL) and the product was extracted with diethyl ether (2x10 mL). The combined organic extracts were dried and concentrated in vacuo in a residue that was purified by flash chromatography (CH / AcOEt 95: 5) to give the title compound (184 mg) as a colorless oil.

NMR (d_ {6} -DMSO): δ (ppm) 8.05 (s, 1 H); 7.9 (s, 2H); 3.6 (s, 3H); 1.6 (s, 6H).

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Intermediate compound 70

Acid 2- (3,5-bis-trifluoromethyl-phenyl) -2-methyl-propionic

A solution of the methyl ester of 2- (3,5-bis-trifluoromethyl-phenyl) -2-methyl-propionic acid (intermediate 69-184 mg) and potassium hydroxide (131 mg) in MeOH (2.5 mL) It was heated at reflux for 1 hour, then allowed to cool to rt and acidified to pH = 3 with a 10% hydrochloric acid solution and extracted with AcOEt (2x10 mL). The combined organic extracts were dried and concentrated in vacuo in a residue that was purified by flash chromatography (CH / AcOEt from 8: 2 to 6: 4) to give the title compound (141 mg) as a white solid.

NMR (d_ {6} -DMSO): δ (ppm) 8.05 (s, 1 H); 7.9 (s, 2H); 1.6 (s, 6H).

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Intermediate compound 71

1- (Benzyloxycarbonyl) -3- (S) - (4-fluoro-2-methyl-phenyl) -piperazine

THF borane (23.16 mL) was added to a solution of intermediate 39 (964 mg) in dry THF (3 mL) previously cooled to 0 ° C under a nitrogen atmosphere. The mixture was heated at 80 ° C for 4 h. MeOH (4 mL) was added and the mixture was concentrated in vacuo . The residue was treated with HCl in Et2O (38 mL) and the solution was heated at 45 ° C for 1 h. The mixture was filtered to give 2- (S) - (4-fluoro-2-methyl-phenyl) -piperazine dihydrochloride (944 mg).

A solution of benzylchloroformate (376 µL) in dry DCM (20 mL) was added dropwise to a solution of 2- (S) - (4-fluoro-2-methyl-phenyl) -piperazine dihydrochloride (700 mg) and TEA (1.1 mL) in DCM (30 mL) previously cooled to 0 ° C under a nitrogen atmosphere. The mixture was stirred at rt for 2 h, then washed with brine. The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (from CH / AcOEt 1: 1 to 100% AcOEt) to give the title compound (750 mg) as a colorless oil.

NMR (d_ {6} -DMSO): δ (ppm) 7.51 (dd, 1H); 7.36-7.28 (m, 5H); 6.95 (m, 2H); 5.1 (dd, 2H); 3.92 (m, 2H); 3.74 (dd, 1 H); 2.95 (dd, 1 H); 2.91 (dt, 1 H); 2.72 (dt, 1 H); 2.62 (t, 1 H); 2.29 (s, 3 H).

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Intermediate compound 72

Acid benzyl ester 4- [1- (3,5-Bis-Trifluoromethyl-phenyl) -1-methyl-ethylcarbamoyl] -3- (S) - (4-fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid

TEA (145 µL) and diphenylphosphorylazide (169 µL) were added to a solution of intermediate 70 (96 mg) in dry toluene (1.5 mL) previously cooled to 0 ° C under a nitrogen atmosphere. The solution was stirred at rt for 3 h, intermediate 71 (96 mg) was added and the mixture was heated at 100 ° C for 1 h. The mixture was allowed to cool to rt and was partitioned between water and AcOEt. The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH / AcOEt 7: 3) to give the title compound (140 mg) as a stick yellow gum.

NMR (d_ {6} -DMSO): δ (ppm) 7.8 (s, 2H); 7.78 (s, 1 H); 7.38-7.22 (m, 5H); 7.21 (dd, 1 H); 6.95 (dd, 1 H); 6.84 (dt, 1 H); 6.52 (s, 1 H); 5.18 (t, 1 HOUR); 5.05 (s, 2H); 3.89 (dt, 1 H); 3.79 (dd, 1 H); 3.72 (dt, 1 H); 3.57 (dd, 1 H); 3.44 (dt, 1 H); 3.28 (broad t, 1H); 2.23 (s, 3 H); 1.55 (s, 3H); 1.5 (s, 3H).

MS: m / z = 626 [MH] +.

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Intermediate compound 73

Acid benzyl ester 4 - {[1- (3,5-bis-trifluoromethyl-phenyl) -1-methyl-ethyl] -methyl-carbamoyl} -3- (S) - (4-fluoro-2-methyl-phenyl) -piperazine- 1-carboxylic

Sodium tert -butoxide (53 mg) was added to a solution of intermediate 72 (140 mg) in dry THF (1.5 mL). The solution was stirred at rt for 30 min., Then methyl iodide (69 µL) was added and stirring was continued for 18 h. More sodium tert-butoxide (42 mg) and methyl iodide (140 µL) were added and the mixture was heated at 70 ° C for 3 h and then allowed to stir at rt for 18 h. The mixture was divided between water and AcOEt (2x10 mL). The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH / AcOEt 9: 1) to give the title compound as a colorless gum (58 mg).

NMR (d_ {6} -DMSO): δ (ppm) 7.81 (s, 2H); 7.78 (s, 1 H); 7.32-7.25 (m, 6H); 6.9 (dd, 1 H); 6.85 (td, 1 H); 5.08 (s, 2 H); 4.64 (dd, 1 H); 3.58 (m, 3H); 3.43 (m, 3 H); 3.0 (s, 3H); 2.18 (s, 3 H); 1.57 (s, 3 H); 1.51 (s, 3H).

MS: m / z = 640 [MH] +.

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Intermediate compound 74

Acid methyl ester 2- (3,5-bis-trifluoromethyl-phenyl) -3-methyl-butyric acid

Sodium bis (trimethylsilyl) -amide (1.0 M in THF-177 µL) was added dropwise to a solution of (3,5-bis-trifluoromethyl-phenyl) -acetic acid methyl ester (389 mg ) in dry THF (2 mL) at 0 ° C, under a nitrogen atmosphere. After ten minutes, isopropyl iodide (143 µL) was added and the reaction mixture was stirred at 0 ° C for 30 min. More isopropyl iodide (143 µL) was added and the solution was stirred at rt for 1 hour. The reaction was quenched with a 2N hydrochloric acid solution (2 mL) and the product was extracted with Et2O (2x). The combined organic extracts were dried and concentrated in vacuo in a residue that was purified by flash chromatography (CH / AcOEt 95: 5) to give the title compound (184 mg) as an oil.
colorless.

NMR (d_ {6} -DMSO): δ (ppm) 8.05 (broad s, 3H); 3.76 (d, 1 H); 3.67 (s, 3 H); 2.33 (m, 1 H); 1.01 (d, 3H); 0.69 (d, 3H).

MS: m / z = 328 [M] +.

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Intermediate compound 75

Acid 2- (3,5-bis-trifluoromethyl-phenyl) -3-methyl-butyric acid

A solution of intermediate 74 (280 mg) and potassium hydroxide (191 mg) in MeOH (4 mL) was heated to reflux for 1 hour, then allowed to cool to rt and acidified to pH = 3 with an acid solution 10% hydrochloric and was extracted with AcOEt (2x10 mL). The combined organic extracts were dried and concentrated in vacuo to give the title compound (250 mg) as a white solid.

NMR (d_ {6} -DMSO): δ (ppm) 8.05 (broad s, 3H); 3.76 (d, 1 H); 2.32 (m, 1 H); 1.01 (d, 3H); 0.65 (d, 3H).

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Intermediate compound 76

Acid tert-butyl ester 4- [1- (3,5-Bis-Trifluoromethyl-phenyl) -2-methyl-propylcarbamoyl] -3- (4-fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid

TEA (133 µL) and diphenylphosphorylazide (156 µL) were added to a solution of intermediate 75 (78 mg) in dry toluene (1 mL) previously cooled to 0 ° C under a nitrogen atmosphere. The solution was stirred at rt for 3 h, then intermediate 63 (80 mg) was added and the mixture was heated at 100 ° C for 2 h. The mixture was allowed to cool to rt and was partitioned between water and AcOEt. The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH / THF 7: 3) to give the title compound (140 mg) as a yellow gum.

IR (nujol) 3400 (NH), 1699 (C-O) cm -1.

NMR (d6 -DMSO): δ (ppm) 7.93 (s, 1H + 1H); 7.84 (s, 2H); 7.78 (s, 2H); 7.13 (dd, 1H + 1H); 6.95 (dd, 1H + 1H); 6.83 (m, 1H + 1H); 6.51 (d, 1 H); 6.41 (d, 1 H); 5.2 (t, 1 H); 5.16 (t, 1 H); 4.57 (t, 1 H); 4.48 (t, 1 H); 3.9-3.17 (m, 6H + 6H); 2.3 (s, 3H); 2.24 (s, 3 H); 2.0-1.96 (m, 1H + 1H); 1.28-1.27 (d, 9H + 9H); 0.87 (d, 3H); 0.74 (d, 3 H); 0.64 (d, 3 H); 0.62 (d, 3H). MS: m / z 606 [MH] +.

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Intermediate compound 77

4 - ({[1- (3,5-Bis-Trifluoromethyl-phenyl) -2-methyl-propyl] -methyl-carbamoyl] tert -butyl ester]} - 3- (4-fluoro-2-methyl- phenyl) -piperazine-1-carboxylic acid (77th diastereoisomer A) 4 - {[1- (3,5-Bis-Trifluoromethyl-phenyl) -2-methyl-propyl] -methyl-carbamoyl]} -3- (4-fluoro-2-methyl-phenyl) tert -butyl ester ) -piperazine-1-carboxylic acid (77b diastereoisomer B)

Sodium tert-butoxide (55 mg) was added to a solution of intermediate 76 (140 mg) in dry THF (1.5 mL). The solution was stirred at rt for 30 min., Then methyl iodide (72 µL) was added and stirring was continued for 18 h. More sodium tert -butoxide (55 mg) and methyl iodide (72 µL) were added and the mixture was stirred at rt for 3 h. The mixture was divided between water and AcOEt (2x). The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH / AcOEt 9: 1) to give the title compound 77a (35 mg) and the title compound 77b (37 mg) as a gum colorless

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Intermediate 77a : TIc: CH / AcOEt 8: 2 Rf = 0.62.

NMR (d_ {6} -DMSO): δ (ppm) 8.0 (s, 1 H); 7.91 (broad s, 2H); 7.21 (m, 1 H); 6.95-6.83 (m, 2H); 4.65 (broad m, 1H); 4.25 (m width, 1H); 3.68 (m, 2H); 3.25-2.81 (m + m + s, 7H); 2.32 (s, 3 H); 1.38 (s, 9H); 0.68 (d, 3H); 0.64 (d, 3H).

MS: m / z = 620 [MH] +.

Intermediate 77b : TIc: CH / AcOEt 8: 2 Rf = 0.62

T.I.c .: CH / AcOEt 8: 2 Rf = 0.73

NMR (d6 -DMSO): δ (ppm) 7.96 (broad s, 1H); 7.79 (broad s, 2H); 6.99 (m, 1 H); 6.93 (m, 1 H); 6.6 (m, 1 H); 4.87 (d, 1 H); 4.27 (m, 1 H); 3.7-3.2 (m width + m width + s + s, 10H); 1.39 (s, 9H); 0.88 (d, 3H); 0.73 (d, 3H). MS: m / z = 620 [MH] +.

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Intermediate compound 78

(3,5-bis-Trifluoromethyl-benzylidene) -methylamine

A solution of 3,5-bis (trifluoromethyl) -benzaldehyde (412 µL) in dry THF (5 mL) was added dropwise to a solution of methylamine (2M in MeOH-3.12 mL) in dry THF (5 mL) at 23 ° C under a nitrogen atmosphere. The reaction mixture was stirred overnight, then the solvent was evaporated in vacuo to give the title compound (385 mg) as a colorless oil.

NMR (CDCl3): δ (ppm) 8.4 (s, 1H); 8.2 (s, 2H); 7.9 (s, 1 H); 3.6 (s, 3H).

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Intermediate compound 79

[(3,5-bis-Trifluoromethyl-phenyl) -cyclopropyl-methyl] -methylamine

A solution of cyclopropyl bromide (518 µL) in dry diethyl ether (15 mL) was added dropwise to magnesium chips (186 mg) previously heated at 40 ° C under a nitrogen atmosphere. The reaction mixture was refluxed for 2 hours, then allowed to cool to rt and decanted from excess magnesium. The cyclopropyl magnesium bromide thus obtained was added to a suspension of copper iodide (614 mg) in dry THF (5 mL) previously cooled to -50 ° C under a nitrogen atmosphere. The reaction mixture was stirred at -50 ° C for 20 min, then the temperature was brought to -78 ° C and boron trifluoride etherate (408 µL) was added. After 5 minutes, intermediate 78 (330 mg) was added dropwise and the reaction mixture was stirred at -50 ° C for 3 hours. The reaction was quenched with a mixture of ammonia (30% in water -10 mL) and saturated ammonium chloride solution (10 mL), extracted with petroleum ether (2x20 mL) and concentrated in vacuo . Then, a solution of 1N hydrochloric acid was added until pH = 3, the aqueous phase was washed with petroleum ether (2x20 mL), then it was basified with solid potassium hydroxide until a pH = 9. After extraction with AcOEt (2x20 mL), the organic layer was dried and concentrated in vacuo to give the title compound (126 mg) as a stick yellow oil.

NMR (d6 -DMSO): δ (ppm) 8.03 (s, 2H); 7.94 (s, 1 H); 2.96 (d, 1 H); 2.4 (broad s, 1H); 2.11 (s, 3 H); 0.92 (m, 1 H); 0.54 (m, 1 H); 0.38 (m, 1 H); 0.29 (t, 2H). MS (ES / +): m / z = 298 [MH] +.

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Intermediate compound 80

4 - {[(3,5-Bis-Trifluoromethyl-phenyl) -cyclopropyl-methyl] -methyl-carbamoyl} -3- (4-fluoro-2-methyl-phenyl) -piperazine-1 acid tert - butyl ester -carboxylic (diastereoisomer A)

A solution of triphosgene (45 mg) in dry DCM (0.5 mL) was added dropwise to a solution of the compound intermediate 63 (100 mg) and ASD (95 µL) in dry DCM (1.5 mL) previously cooled to 0 ° C under a nitrogen atmosphere. The reaction mixture was stirred at 0 ° C for 2 hours, then it was added a solution of and DIPEA (237 µL) in dry acetonitrile (2 mL). The reaction was heated to 70 ° C to evaporate the DCM, then intermediate 79 (110 mg) and the mixture of reaction was refluxed overnight.

The mixture was diluted with AcOEt (10 mL), washed with a solution of 2N hydrochloric acid (10 mL) and brine (10 mL), dried and concentrated in vacuo in a residue, which was purified by flash chromatography (CH / AcOEt from 8: 2 to 7: 3) to provide the title compound (10 mg)

NMR (d_ {6} -DMSO): δ (ppm) 7.77 (s, 1 H); 7.73 (s, 2H); 7.24 (m, 1 H); 6.85 (m, 2H); 4.56 (d, 1 H); 4.46 (broad m, 1H); 3.94 (m, 2H); 3.23 (m, 2 H); 3.05 (m, 2H); 2.96 (s, 3 H); 2.4 (s, 3H); 1.47 (s, 9H); 1.25 (m, 1 H); 0.84 (m, 1 H); 0.43 (m, 2H); 0.18 (m, 1 H).

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Intermediate compound 81

(S) -Dihydrochloride 3- (4-fluoro-2-methyl-phenyl) -piperazine

To a solution of intermediate 39 (60.35 g) in dry THF (180 ml), at 0-3 ° C, under N 2, 1 M BH 3 / THF (1,220 ml) was added dropwise ). The solution was refluxed for 4 hours, then cooled to 0-3 ° C and methanol (240 ml) was added. The reaction mixture was heated to room temperature and then concentrated to dryness. The residue was redissolved in methanol (603.5 ml), an excess of 1N HCl in Et2O (1.207 ml) was added and the mixture was refluxed for 2 hours and then cooled to 3 ° C for 4 hours. The suspension was filtered to obtain a white solid material, which was washed with Et2O (60.35 ml) and dried to give the title compound (72.02 g).

1 H-NMR (DMSO) δ (ppm) 11.0-9.5 (broad signal, 4H); 7.99-7.19 (dd-m, 3H); 4.96 (dd, 1 H); 3.65-3.15 (m, 6H); 2.42 (s, 3 H).

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Intermediate compound 82

(R) -3,5-Bis-trifluoromethyl-phenyl) -ethyl] -methyl-amine

To a solution of 3,5-bis-trifluoromethyl-acetophenone (300 g) in MeOH (1,120 ml) was added dropwise a solution of 8 M methyl amine in EtOH (372 ml) for 15 min at 25 ° C under N 2. The mixture was stirred for 24 h at 25 ° C under N_ {2}. Then NaBH_ {4} was added in portions for 30 min (27.9 g) at 0 ° C. A second amount of NaBH_ {4} was added for 30 min (17.1 g) and the mixture was stirred for 1.5 h additional.

The mixture was concentrated by evaporation of 600 ml. of the solvent in vacuo and then slowly poured into a mixture of AcOEt (1,500 ml) and saturated NH4Cl (750 ml) and water (750 ml). The water phase was extracted after return with AcOEt (1,500 ml). The combined organic phases were washed with a mixture of water and brine (150 ml / 150 ml) and then evaporated to obtain the [(3,5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-amine (305 g) as a yellow oil.

To a solution of [(3,5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-amine (245.6 g) in EtOAc (2,380 ml) was added L (-) - malic acid in portions (118 g) . The suspension was stirred for 2 h at 25 ° C and then for 3 h at 0 ° C. The suspension was filtered and the cake was washed with EtOAc (240 ml). The solid material was dried under vacuum to obtain the L (-) - [(3,5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-amine crude (135.3 g) malate as a white solid material , which was suspended in ethyl acetate (1760 ml), then heated to reflux until a complete solution was obtained and then cooled to 25 ° C. The suspension was filtered, washed with ethyl acetate (135 ml) and then dried to obtain L (-) - [(3,5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-amine (128) , 5 g). The solid material was stirred in a mixture of 10% v / v NaOH (720 ml) and ethyl acetate (650 ml). The organic phase was washed with water (720 ml) and then concentrated to provide the title compound (82.2 g).

1 H-NMR (DMSO): δ (ppm) 7.99 (s, 2H); 7.85 (s, 1 H); 3.78 (q, 1 H); 2.34 (s, 1 H); 2.09 (s, 3H); 1.23 (d, 3H).

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Example one

Hydrochloride (3,5-Bistrifluoromethyl-benzyl) -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid

A solution of intermediate 13 (0.05 g) in EtOH (10 mL) was hydrogenated at atmospheric pressure for 3 h, in the presence of 10% Pd / C (10 mg) as catalyst. The catalyst was filtered and the solvent was evaporated. The unpurified residue dissolved in diethyl ether was added and then to a sol. 1M HCl in Et2O (0.1 mL). The precipitate formed was filtered and washed with diethyl ether to obtain the title compound (0.02 g) as a white powder.

m.p. > 220 ° C;

NMR (DMSO) δ (ppm) 9.33 (m wide, 1H), 9.18 (m wide, 1H), 7.96 (s, 1H), 7.59 (s, 2H), 7.33 (dd, 1H), 6.99 (d, 1H), 6.85 (t, 1H), 4.63 (d, 1H), 4.53 (d, 1H), 4.37 (d, 1H) , 3.52 (d, 1H.), 3.4-3.2 (m, 2H), 3.25 (m, 1H), 3.04 (t, 1H), 3.0-2.8 ( m, 1H), 2.93 (s, 3H), 2.38 (s, 3H). IR (Nujol) (cm -1) 3200, 1659; MS ( m / z ) 478 [M-Cl] +.

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Example 2

Hydrochloride (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (3-Isopropyl-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 14 (0.353 g) in EtOH anh. (5.7 mL), at rt, in N2, 10% Pd / C (175 mg, 50% by weight) was added. The black suspension was placed under an H2 atmosphere and stirred for 3 h. The catalyst was then filtered on Celite and the Celite cake was rinsed with EtOH. Then 1.0M HCl in Et2O (1.13 mL) was added. The solvent was evaporated and the oil obtained was triturated with Et2O. The solid was filtered, rinsed with Et2O and dried under vacuum. The title compound was obtained as a gray solid (104 mg).

m.p. 77-80 ° C;

NMR (CDCl3): δ (ppm) 8.95 (broad s, 2H), 7.97 (s, 1H), 7.75 (s, 1H), 7.22-7.08 (m, 4H), 4.58-4.41 (2d, 2H), 4.50 (dd, 1H), 3.44 (m, 1H), 3.4-3.1 (m, 5H), 2.84 (s, 3H), 2.80 (m, 1H), 1.12 (d, 3H), 1.07 (d, 3H).

IR (Nujol) (cm -1) 3437, 1653; MS ( m / z ) 488 [M-Cl] +.

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Example 3

Hydrochloride (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (2-Isopropyl-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 15 (0.108 g) in EtOH anh. (2.0 mL), at rt, in N2, 10% Pd / C (20 mg, 20% by weight) was added. The black suspension was placed under an H2 atmosphere and stirred for 3 h. The catalyst was then filtered on Celite and the Celite cake was rinsed with EtOH. Then 1.0M HCl in Et2O (350 µL) was added. The solvent was evaporated and the oil obtained was triturated with Et2O. The solid was filtered, rinsed with Et2O and dried under vacuum. The title compound was obtained as a brown solid (29 mg).

m.p. 108-110 ° C; NMR (CDCl 3): δ (ppm) 9.15 (broad d, 1H), 8.92 (broad d, 1H), 7.97 (s, 1H), 7.66 (s, 2H), 7.30 (m, 1H), 7.27 (m, 1H), 7.19 (dt, 1H), 7.03 (dt, 1H), 4.69 (dd, 1H), 4.55 (2d, 2H), 3.53 (m, 1H), 3.39 (m, 3H), 3.19 (broad d, 1H), 3.04 (dt, 1H), 2.92 (m, 4H), 1.24 (d, 3H), 1.20 (d, 3H).

IR (Nujol) (cm -1) 3441, 1662. MS ( m / z ) 489 [M-Cl] +.

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Example 4

Hydrochloride (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (4-Fluoro-3-methyl-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 16 (0.226 g) in EtOH anh. (3.7 mL), at t.a., in N2, was added 10% Pd / C (23 mg, 10% by weight). The black suspension was placed under an atmosphere of H2 and was stirred for 3 h. Catalyst it was then filtered in Celite and Celite's cake was clarified with EtOH. then 1.0M HCl in Et2O (740 µL) was added. The solvent was evaporated and the oil obtained was treated with Et 2 O. The solid obtained was filtered, rinsed with Et2O and it was dried under vacuum to give the title compound as a white solid (112 mg).

m.p. 70-72 ° C;

NMR (CDCl3): δ (ppm) 9.08 (m, 2H), 7.97 (s, 1H), 7.67 (s, 2H), 7.19 (m, 1H), 7.14 (m, 1H), 7.01 (t, 1H), 4.59 (d, 1H), 4.43 (m, 1H), 4.40 (d 1H), 3.1-3.5 (m, 6H), 2.92 (s, 3H), 2.14 (s, 3H).

IR (Nujol) (cm -1) 3406, 1653; MS ( m / z ) 478 [M-Cl] +.

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Example 5

Hydrochloride (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (2,4-Difluoro-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 17 (0.134 g) in EtOH anh. (2.0 mL), at rt, in N2, 10% Pd / C (27 mg, 20% by weight) was added. The black suspension was placed under an H2 atmosphere and stirred for 3 h. The catalyst was then filtered on Celite and the Celite cake was rinsed with EtOH. Then 1.0M HCl in Et2O (436 µL) was added. The solvent was evaporated and the oil obtained was triturated with Et2O. The solid was filtered, rinsed with Et2O and dried under vacuum. The title compound was obtained as a yellow solid (112 mg).

m.p. 220-230 ° C; NMR (CDCl 3): δ (ppm) 9.08-9.3 (m, 2H), 7.97 (s, 1H), 7.62 (s, 2H), 7.44 (m, 1H), 7.18 (m, 1H), 6.95 (m, 1H), 4.65 (m, 1H), 4.3-4.65 (dd, 2H), 3.2-3.6 (m, 4H), 3.07 (m, 2H), 2.92 (s, 3H).

IR (Nujol) (cm -1) 3400, 1656; MS ( m / z ) 482 [M-Cl] +.

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Example 6

Hydrochloride (3,5-bis-trifluoromethyl-benzyl) -amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid

A solution of intermediate 18 (0.086 g) in EtOH (10 ml) was hydrogenated at atmospheric pressure for 2 h, in the presence of 10% Pd / C (20 mg) as catalyst. The catalyst was filtered and the solvent was evaporated. The unpurified residue was dissolved in Et2O and then a sol was added. 1M HCl in Et2O (0.1 ml). The solvent was evaporated to obtain the title compound (0.05 g) as a white solid.

NMR (DMSO) δ (ppm) 9.06 (m, 1H), 8.88 (m, 1H), 7.91 (s, 1H), 7.77 (s, 2H), 7.42 (t, 1H), 7.22 (dd, 1H), 7.03 (m, 1H), 6.94 (t, 1H), 5.22 (t, 1H), 4.34 (m, 2H), 3.98 (m, 1H), 3.64 (m, 1H), 3.4-3.2 (m, 2H), 3.22 (m, 2H), 2.32 (s, 3H).

IR (Nujol) (cm -1) 3360, 1645. MS ( m / z ) 464 [M-Cl] +.

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Example 7

Hydrochloride (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid (+) - 2- (R) - (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic

A solution of intermediate 20a (0.120 g) in EtOH (5 mL) was hydrogenated at atmospheric pressure for 4 h, in the presence of 10% Pd / C (25 mg). Then, the catalyst was filtered and the solvent was evaporated. The unpurified product was dissolved in Et2O and then a 1M solution of HCl in Et2O (0.3 mL) was added. Then the precipitate was filtered and washed with Et2O to obtain the title compound (0.057 g) as a white solid.

mp> 220 ° C;

NMR (DMSO) δ (ppm) 9.11 (m, 1H); 8.83 (m, 1 HOUR); 7.96 (s, 1 H); 7.59 (s, 2H); 7.34 (dd, 1 H); 6.94 (dd, 1 H); 6.86 (m, 1 H); 4.65-4.35 (dd, 2H); 4.49 (m, 1 H); 3.54 (m, 1 HOUR); 3.44-3.01 (m, 4H); 2.93 (s, 3 H); 2.90 (m, 1 H); 2.38 (s, 3 H).

MS ( m / z ) 479 [MH-Cl] +;

[α D] 20 = + 69.5 C = 0.27 (g / 100 ml) CHCl3.

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Example 8

Hydrochloride (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid (-) - 2- (S) - (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic

Method TO

A solution of intermediate 20b (0.110 g) in EtOH (5 mL) was hydrogenated at atmospheric pressure for 4 h, in the presence of 10% Pd / C (25 mg). Then the catalyst was filtered and the solvent was evaporated. The unpurified product was dissolved in Et2O and then a 1M solution of HCl in Et2O (0.3 mL) was added. The precipitate was then filtered and washed with diethyl ether to obtain the title compound (0.045 g) as a white solid.

Method B

A solution of intermediate 37a (0.24 g) in EtOH (4 mL) was hydrogenated at atmospheric pressure for 3 h, in the presence of 10% Pd / C (73 mg) as catalyst. The catalyst was filtered and the solvent was evaporated. The unpurified residue was dissolved in Et2O and then a sol was added. 1M HCl in Et2O (0.58 mL). The precipitate formed was filtered and washed with diethyl ether to obtain the title compound (0.04 g) as a white powder.

Method C

To intermediate 39 (2.37 g) was added TEA dropwise (3.15 mL) in dry DCM (57 mL), at 0 ° C. It was after a solution of triphosgene (1.502 g) in dry DCM (12 mL) added Under an inert atmosphere. The temperature was maintained at 0 ° C. for 3 h, before the addition of DIPEA (4 mL) followed by 3,5-bis-trifluoromethylbenzyl-N-methyl-amine  (4.62 g) in acetonitrile. (142 mL). The reaction mixture was heated at reflux for 3 h then cooled to temperature ambient diluted with DCM (25 mL) and washed with a 1N solution of HCl (25 mL), H2O (25 mL) and brine (25 mL) in sequence. The organic phase was dried and the unpurified product obtained after evaporation of the solvent it was purified by Flash chromatography (from AcOEt / CH 4: 1 to pure AcOEt) to give (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -3-oxo-piperazine-1-carboxylic  as a foam (1.79 g).

This compound was reduced with BH 3 .THF (17.6 mL) following the standard procedure (4 h reflux in 10 ml of THF, after preparation with 6 mL of 37% HCl and subsequent neutralization with 5 g of Solid NaHCO3) to give the title compound (1.16 g).

mp> 220 ° C; NMR (DMSO) δ (ppm) 9.11 (m, 1 H); 8.83 (m, 1 H); 7.96 (s, 1 H); 7.59 (s, 2H); 7.34 (dd, 1 H); 6.94 (dd, 1 H); 6.86 (m, 1 H); 4.65-4.35 (dd, 2H); 4.49 (m, 1 H); 3.54 (m, 1 H); 3.44-3.01 (m, 4H); 2.93 (s, 3H); 2.90 (m, 1 H); 2.38 (s, 3 H).

MS ( m / z ) 479 [MH-Cl] +;

[α D] 20 = - 72.6 C = 0.27 (g / 100 ml) CHCl3.

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Example 9

Hydrochloride [1- (3,5-bis-trifluoromethyl-phenyl) ethyl] -methyl-amide of acid 2- (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid

A solution of intermediate 22a (0.05 g) in EtOH (5 ml) was hydrogenated at atmospheric pressure for 1½ h, in the presence of 10% Pd / C (15 mg). Then the catalyst was filtered off and the solvent evaporated. The crude product was dissolved in Et2O and then a 1M solution of HCl in Et2O (0.5 ml) was added. Then, the precipitate was filtered and washed with Et2O to obtain the title compound (0.025 g) as a white powder.

NMR (CDCl3) δ (ppm) 10.2 (b, 1H); 7.78 (s, 1 H); 7.54 (s, 2H); 7.13 (dd, 1 H); 6.88 (dd, 1 H); 6.82 (m, 1 HOUR); 5.48 (q, 1 H); 4.57 (m, 1 H); 3.6-3.5 (m, 2H); 3.38 (m, 2 H); 3.3-3.0 (m, 2H); 2.71 (s, 3 H); 2.48 (s, 3H); 1.44 (d, 3 H).

IR (CDCl 3) 1663

MS [Mass Spectrum] ( m / z ): 491 [M-Cl] +

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Example 10

Hydrochloride [1- (3,5-bis-trifluoromethyl-phenyl) ethyl] -methyl-amide of acid 2- (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid

A solution of intermediate 22b (0.05 g) in EtOH (5 ml) was hydrogenated at atmospheric pressure for 1½ h, in the presence of 10% Pd / C (15 mg). Then the catalyst was filtered off and the solvent evaporated. The crude product was dissolved in Et2O and then a 1M solution of HCl in Et2O (0.5 ml) was added. Then, the precipitate was filtered and washed with Et2O to obtain the title compound (0.057 g) as a white powder.

NMR (CDCl3) δ (ppm) 10.2 (signal wide, H); 7.74 (s, 1 H); 7.41 (s, 2H); 7.10 (m, 1 H); 6.88 (m, 1 H); 6.80 (m, 1 H); 5.58 (q, 1 H); 4.85 (m, 1 H); 3.7-2.9 (m, 6H); 2.80 (s, 3 H); 2.49 (s, 3 H); 1.44 (d, 3 H).

IR (CDCl 3) 1662

MS ( m / z ): 491 [M-Cl] +

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Example eleven

(3,5-bis-Trifluoromethyl-benzyl) -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 32 (813 mg) in THF anh. (6.6 mL), at rt, in N2, 1M BH3 .THF in THF (9.9 mL) was added. The solution was heated at reflux for 3 h. It was then brought to rt and 1N HCl (4 mL) was added slowly to destroy the borane complexes. The reaction mixture was stirred at rt for 18 h. THF was evaporated and the aqueous phase was basified with 10% NaOH. It was then extracted with EtOAc (3x). The combined organic extracts were dried, the solids were filtered and the solvent was evaporated. The title compound was used in the next step (790 mg) without further purification.

NMR (CDCl3): δ (ppm) 7.77 (s, 1H), 7.49 (s, 2H), 7.33 (m, 1H), 6.86 (m, 1H), 6.82 (m, 1H), 4.65-4.46 (2d (AB), 2H), 4.46 (m, 1H), 3.40-2.85 (m, 6H), 2.97 (s, 3H), 2.66 (s, 3H).

IR (CDCl 3, cm -1): 1653.

MS ( m / z ): 478 [MH] +.

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Example 12

Hydrochloride (3,4-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (4-fluoro-phenyl) -piperazine-1-carboxylic

A 1M solution of BH3. In THF (1.88 mL) was added very carefully to a solution of intermediate 33 (0.18 g) in dry THF (8 mL) under an inert atmosphere; and the reaction mixture was refluxed 3 h. After completion of the reduction, 37% HCl (3 mL) was added and the reaction mixture was refluxed 2 h. THF was removed under reduced pressure, water (3 mL) was added and the aqueous solution was basified using Na2CO3; It was then extracted with DCM, washed with brine and dried. The unpurified product was purified by flash chromatography (AcOEt / MeOH 8: 2) to provide the free amine that was treated with a 1M solution of HCl in Et2O (0.3 mL) to provide the title compound (0 , 05 g) as a white solid.

mp> 200 ° C;

NMR (DMSO) δ (ppm): 9.08 (broad s, 2H), 7.97 (s, 1H), 7.66 (s, 2H), 7.35 (m, 2H), 7.10 (m, 2H), 4.60 (d, 1H), 4.46 (dd, 1H), 4.39 (d, 1H), 3.50-3.10 (m, 6H), 2.92 (s, 3 H).

IR (Nujol) (cm -1) 3437, 1653;

MS: 464 [M-Cl] +.

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Example 13

Hydrochloride (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2-phenyl-piperazine-1-carboxylic

To a stirred solution of intermediate 34 (0.382 g) in THF (10 mL) was added a 1M solution of BH 3 in THF (1.66 mL). The mixture was then refluxed for 3 h. The temperature was then reduced, and the reaction was quenched with a solution of 37% HCl (5 mL) and stirred at room temperature overnight. The solution was then basified with NaOH and the product was extracted with DCM, dried and concentrated under reduced pressure to give an oil. The oil was then dissolved in Et2O and a 1M solution of HCl in Et2O (1.6 mL) was added. After a few minutes the solution was concentrated, and the product was triturated from petroleum ether to give the title compound (0.300 g) as a solid.

NMR (CDCl3): δ (ppm); 10.15 (b, 2H); 7.75 (s, 1 H); 7.44 (s, 2H); 7.3 (m, 5H); 4.80-4.34 (m, 3H); 3.80-3.00 (m, 6H); 2.93 (s, 3 H);

MS ( m / z ): 445 [M-Cl] +.

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Example 14

Hydrochloride (3,5-Bistrifluoromethyl-benzyl) -methyl-amide of the acid 2- (2,4-Dichloro-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 35 (0.22 g) in THF (15 mL) a 1M solution of borane in THF (1.2 mL) was added and the reaction mixture was stirred at reflux for 3 h, then cooled at rt, 37% HCl (3 mL) was added dropwise and the reaction mixture was stirred for 3 h. The solvent was evaporated and the unpurified residue was diluted with AcOEt and washed with a saturated NaHCO3 solution and brine. The organic phase was dried and concentrated to give the product without purification. The latter was dissolved in Et2O (2 ml), then a sol was added. 1M HCl in Et2O (1 mL). The solution obtained was added dropwise in oil (30 mL) and the precipitate formed was filtered to obtain the title compound (0.06 g, white solid).

NMR (DMSO) δ (ppm) 9.25, 9.15 (m + m, 2H), 7.98 (m, 1H), 7.64 (s, 2H), 7.60 (d, 1H), 7.45 (d, 1H), 7.29 (dd, 1H), 4.78 (dd, 1H), 4.63 (d, 1H), 4.35 (d, 1H), 3.59 (d, 1H), 3.40-3.25 (m, 3H), 3.07 (t, 3H), 2.95, 2.93 (s + m, 4H).

IR (Nujol) (cm -1) 3442, 1654;

MS ( m / z ) 515 [M-Cl] +.

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Example fifteen

Hydrochloride (3,5-Bistrifluoromethyl-benzyl) -methyl-amide of the acid 2- (3,4-Dichloro-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 36 (0.13 g) in THF (20 mL) was added a 1M solution of borane in THF (1.96 mL) and the reaction mixture was stirred at reflux for 3 h, then cooled at rt, 37% HCl (5 mL) was added dropwise and the reaction mixture was stirred for 3 h. The solvent was evaporated and the unpurified residue was diluted with AcOEt and washed with a saturated NaHCO3 solution and brine. The organic phase was dried and concentrated to give the product without purification. The latter was dissolved in Et2O (2 mL), then a sol was added. 1M HCl in diethyl ether (1 mL). The solution obtained was added dropwise in petroleum (30 mL) and the precipitate formed was filtered to obtain the title compound (0.016 g, white solid).

NMR (DMSO) δ (ppm) 8.99 (width, 2H), 7.98 (s, 1H), 7.70 (s, 2H), 7.56 (d + d, 2H), 7.31 (dd, 1H), 4.58 (d, 1H), 4.50 (d, 1H), 4.41 (d, 1H), 3.5-3.1 (m, 4H), 2.93 (s, 3H). IR (Nujol) (cm -1) 3436, 1653;

MS ( m / z ) 515 [M-Cl] +.

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Example 16

Hydrochloride [1- (S) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-amide of acid (-) - 2- (S) - (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic

A solution of intermediate 38a (0.08 g) in EtOH (5 ml) was hydrogenated at atmospheric pressure for 4 h, in the presence of 10% Pd / C (50 mg). The catalyst was filtered off and the solvent evaporated. The crude product was dissolved in Et2O and then a 1M solution of HCl in Et2O (0.5 ml) was added. The precipitate was filtered and washed with Et2O to obtain the title compound (0.023 g).

NMR (CDCl3) δ (ppm) 10.5-10.0 (broad signal, 2H); 7.74 (s, 1 H); 7.41 (s, 2H); 7.09 (m, 1 H); 6.88 (m, 1 H); 6.80 (m, 1 H); 5.58 (q, 1 H); 4.85 (m, 1 H); 3.80-3.00 (m, 6H); 2.80 (s, 3 H); 2.49 (s, 3H); 1.53 (d, 3H).

MS ( m / z ): 492

[α] D 20 = -164.9 °, 0.12 (g / 100 ml) of CHCl3.

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Example 17

Hydrochloride [1- (R) - (3,5-bis-trifluoromethyl-phenyl) ethyl] -methyl-amide of acid (+) - 2- (R) - (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic

A solution of intermediate 38b (0.08 g) in EtOH (5 ml) was hydrogenated at atmospheric pressure for 4 h, in the presence of 10% Pd / C (50 mg). The catalyst was filtered off and the solvent evaporated. The crude product was dissolved in Et2O and then a 1M solution of HCl in Et2O (0.5 ml) was added. The precipitate was filtered and washed with Et2O to obtain the title compound (0.020 g).

NMR (CDCl3) δ (ppm) 10.5-10.0 (broad signal, 2H); 7.74 (s, 1 H); 7.41 (s, 2H); 7.09 (m, 1 H); 6.88 (m, 1 H); 6.80 (m, 1 H); 5.58 (q, 1 H); 4.85 (m, 1 H); 3.80-3.00 (m, 6H); 2.80 (s, 3 H); 2.49 (s, 3H); 1.53 (d, 3H).

MS ( m / z ): 492

[α] D 20 = + 207 °, 0.11 (g / 100 ml) of CHCl3.

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Example 18

Acetate salt [1- (R) - (3,5-bis-trifluoromethyl-phenyl) ethyl] -methyl-amide of acid 2- (S) - (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 40a (8.8 g) in dry THF (33 ml) under N 2 BH 3 was added THF (1 M solution in THF-87 ml) and the reaction mixture was stirred at reflux for 3 h, then cooled to t.a. and was added drop to drop HCl (37%, 30 ml) keeping the reaction mixture in a ice bath The reaction mixture was stirred at t.a. for 1 h. Then water (70 ml) was added and solid NaHCO3 was added (35.2 g) in portions until reaching a pH of 6.5. THF evaporated and the aqueous phase was extracted with Et2O (3 x 88 ml). Phases combined organics dried and evaporated to leave an oil colorless (7.37 g).

The crude oil was purified by flash chromatography (with a mixture of AcOEt and MeOH 7: 3). The product obtained was suspended in Et2O (125 ml) and washed with saturated NaHCO3 (2 x 20 ml). The combined transparent organic phases were dried and evaporated to obtain the 2- (S) - (4-Bis-trifluoromethyl-phenyl) ethyl] -methyl-amide acetate salt. -fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid as a white foam (5.27 g). This material (5.27 g) was dissolved in Et2O (79 ml) and acetic acid (613 µl) was added dropwise. The mixture was stirred at rt for 1 h and then at 0 ° C for 1 h. The suspension was filtered to give the title compound (4.366 g) as a white solid material.

NMR (1 H, DMSO-d 6): δ (ppm) 7.98 (s, 1 H); 7.70 (s, 2 H); 7.87 (m, 1 H); 6.91 (m, 1 HOUR); 6.77 (m, 1 H); 5.29 (q, 1 H); 4.23 (dd, 1 H); 3.2-2.6 (m, 6H); 2.68 (s, 3 H); 2.3 (s, 3H); 1.89 (d, 3H).

MS ( m / z ): 492 [M-CH 3 COO] +.

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[α] D 20 = -120.4 ° Solvent (CHCl3); Source: Na; Cell volume [ml]: 1; Path length in cell [dm]: 1; Temperature in the cell [° C]: 20; Wavelength [nm]: 589.

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Example 19

Acetate [1- (S) - (3,5-bis-trifluoromethyl-phenyl) ethyl] -methyl-amide of acid 2- (S) - (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 40b (2.57 g) in dry THF (15.5 ml), at 0 ° C, under N2, was added BH 3 • THF (1 M solution in THF) and then heated to reflux for 3 h. He was then taken back to t.a. and 37% HCl (9 ml) was added slowly maintaining the mixture of reaction in an ice bath. The reaction mixture was stirred at t.a. for 1 h. Then water (20.5 ml) was added and added in NaHCO3 portions solid until a pH of 7 is reached.

The THF was evaporated and the aqueous phase was extracted with Et2O (3 x 25.7 ml). The combined organic phases were dried and evaporated to leave a yellow oil (2.34 g). This crude oil was dissolved in Et2O (35 ml) and glacial AcOH (0.245 ml) was added dropwise. The mixture was stirred for 2 h at 0 ° C, then filtered, washed with Et2O (10 ml) and dried under vacuum to obtain the title compound as a white solid material (1,349 g).

NMR (1 H, DMSO-d 6): δ (ppm) 7.92 (s, 1 H); 7.58 (s, 1 H); 7.29 (m, 1 H); 6.90 (m, 1 HOUR); 6.77 (m, 1 H); 5.33 (q, 1 H); 4.19 (m, 1 H); 3.2-2.6 (m, 6H); 2.79 (s, 3 H); 2.32 (s, 3 H); 1.89 (s, 3H); 1.48 (d, 3 H).

MS ( m / z ): 492 [M-CH 3 COO] +.

[α] D 20 = + 2.2 °

Solvent (CHCl3); Source: Na; Volume of cell [ml]: 1; Path length in cell [dm]: 1; Temperature in the cell [° C]: 20; Wavelength [nm]: 589.

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Example twenty

Hydrochloride (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 4- (2-amino-acetyl) -2- (S) - (4-fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid

The compound of Example 8 (0.05 g) was dissolved in dry DMF (2 mL), DIPEA (0.019 mL) was added and the solution thus obtained was added to a solution of N- (tert-butoxycarbonyl) glycine (0, 0192 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodimide (0.0214 g) and 1-hydroxybenzotriazole (0.015 g) in dry DMF (5 mL). The reaction mixture was stirred 18 h at room temperature, then diluted with AcOEt (30 mL), washed with water (30 mL), sodium bicarbonate (30 mL) and brine (30 mL). The separated organic layer was dried and evaporated to give an unpurified product, which was purified by flash chromatography (AcOEt). The compound obtained (0.043 g) was dissolved in a 1M solution of HCl in Et2O (5 mL), stirred 0.5 h at room temperature and evaporated to obtain the title compound (0.046 g) as a foam yellow.

NMR (DMSO) δ (ppm) 8.01 (broad s, 3H), 7.88 (s, 1H), 7.67 (s, 2H), 7.33 (m, 1H), 6.95 (m, 1H), 6.83 (m, 1H), 4.60 (m, 1H), 4.60-4.42 (dd, 2H), 4.2-3.3 (m, 6H), 3.2 (m, 2H), 2.89 (s, 3H), 2.4 (s, 3H).

IR (Nujol) (cm -1) 3410, 1660.

MS ( m / z ) 535 [M-Cl] +.

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Example twenty-one

Hydrochloride [1- (3,5-bis-trifluoromethyl-phenyl) -1-methyl-ethyl] -methyl-amide of the acid 2- (S) - (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid

Palladium on carbon (10% -17.5 mg) was added to a solution of intermediate 73 (145 mg) in ethanol (2 mL). The resulting mixture was stirred at 1 atm and rt under a hydrogen atmosphere for 2 h. The mixture was filtered and concentrated in vacuo . The residue was dissolved in Et2O (2 mL) and treated with 1M HCl in Et2O (1 mL), the mixture was stirred at rt for 10 min, then concentrated in vacuo and the residue was triturated with Et 2 O / petroleum to give the title compound (27 mg) as a white solid.

NMR (d_ {6} -DMSO): δ (ppm) 9.15 (broad s, 1H); 8.9 (broad s, 1H); 7.77 (s, 1 H); 7.71 (s, 2H); 7.31 (dd, 1 H); 6.95-6.87 (m, 2H); 4.39 (dd, 1 HOUR); 3.71 (dt, 1 H); 3.35-2.9 (m, 5H); 3.24 (s, 3 H); 2.23 (s, 3 H); 1.49 (s, 3 H); 1.46 (s, 3 H).

MS: m / z = 506 [MH] +.

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Example 22

Dihydrochloride salt (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 4- (2-amino-ethyl) -2- (S) - (4-fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 41 (25 mg) in absolute EtOH (1 mL), at room temperature, 8.03M methylamine in EtOH (48 µL) was added. The reaction mixture was stirred at rt for 5 h. The solvent was evaporated and the unpurified product was purified by flash chromatography (AcOEt / MeOH / NH 4 OH conc. 90: 5: 5). The fractions were recovered and the solvent was evaporated. The residue was dissolved in Et2O and 1.0M HCl in Et2O (150 µL) was added. The yellow precipitate was filtered and dried to give the title compound (19 mg) as a yellow solid.

NMR (DMSO) δ (ppm) 8.12 (broad s, 2H), 7.90 (s, 1H), 7.62 (s, 2H), 7.33 (t, 1H), 6.95 (dd, 1H), 6.83 (td, 1H), 4.69 (m, 1H), 4.62 (d, 1H), 4.41 (d 1H), 3.60-3.10 (m, 10H), 2.94 (s, 3H), 2.40 (s, 3H).

IR (Nujol) (cm -1) 3433-3300, 1651.

MS ( m / z ) 521 [M-2HCl + H] +.

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Example 2. 3

Hydrochloride salt (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -3-methyl-piperazine-1-carboxylic acid

To a solution of intermediate 45 (100 mg) in MeOH anh. (3 mL), in N2, at room temperature, 10% Pd / C (20 mg) was added. The reaction mixture was placed under an atmosphere of H2 and stirred at room temperature for 2 h. The catalyst was filtered on Celite, and the Celite cake was rinsed with AcOEt. The solvent was evaporated and the residue was dissolved in Et2O. 1.0N HCl in Et2O (240 µL) was added and the white precipitate was filtered and rinsed with Et2O. The title compound was obtained (73 mg) as a white solid.

NMR (CDCl3) δ (ppm) 9.31 +9.01 (m, 2H), 7.99 (s, 1H), 7.70 (s, 2H), 7.02 (m, 2H), 6.78 (m, 1H), 4.63 (d, 1H), 4.7-4.3 (dd, 2H), 3.66 (m, 1H), 3.5-2.9 (m, 4H), 3.05 (s, 3H), 2.34 (s, 3H), 1.09 (d, 3H).

IR (Film) (cm -1) 1659.

MS ( m / z ) 692 [MH-Cl] +.

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Example 24

Hydrochloride salt (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (2-methyl-4-fluoro-phenyl) -6-methyl-piperazine-1-carboxylic acid

The BH3 .THF complex (1.25 mL) was added very carefully to a solution of intermediate 47 (0.080 g) in dry THF (5 mL) under an inert atmosphere and the reaction mixture was refluxed for 3 h. After completion of the reduction, 37% HCl (3 mL) was added and the reaction mixture was refluxed for 2 h. THF was removed under reduced pressure, water (3 mL) was added and the aqueous solution was basified by means of Na2CO3, extracted with DCM, washed with brine and dried. The unpurified product was purified by flash chromatography (AcOEt / MeOH 8: 2) to produce a product that was dissolved in Et2O and treated with 1.0M HCl in Et2O (0.3 mL) to give the title compound (0.03 mg).

1 H-NMR (DMSO) δ (ppm) 9.12 (wide s, 1H), 8.88 (wide s, 1H), 7.93 (s, 1H), 7.56 (s, 2H), 7.37 (m, 1H), 6.74 (m, 2H), 4.71 (d, 1H), 4.35 (dd, 1H), 4.36-4.10 (wide m, 1H), 3.35-2.9 (m, 5H), 2.99 (s, 3H), 2.28 (s, 3H), 1.05 (d, 3H).

MS ( m / z ) 492 [M-Cl] +. mp> 200 ° C

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Example 25

Hydrochloride [(1-3,5-bis-trifluoromethyl-phenyl) -cyclopropyl] -methyl-amide of the acid 2- (S) - (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid

HCl conc. (0.27 mL) to a solution of intermediate 53 (90 mg) in methanol (9 mL) and the mixture was refluxed for 15 min. The mixture was concentrated in vacuo and the residue was triturated with Et2O to give the title compound (32 mg) as a white solid.

IR (nujol): 3405 (NH2 +), 1653 (C-O) cm -1;

NMR (DMSO) δ (ppm) 9.42 (broad s, 1H); 9.27 (broad s, 1H); 7.79 (broad s, 1H), 7.45 (dd, 1H); 7.25 (s wide, 2H); 6.94 (m, 2H), 4.52 (dd, 1H), 3.5-3.06 (m, 9H); 2.33 (s, 3H), 1.34 (m, 2H); 1.22 (m, 2H).

MS: m / z = 504 [M-Cl] +.

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Example 26

Hydrochloride [2- (3,5-bis-trifluoromethyl-phenyl) -pyrrolidin-1-yl] - [2- (S) - (4-fluoro-2-methyl-phenyl) -piperazin-1-yl] -methanone  (enantiomer A)

HCl conc. (0.3 mL) to a solution of intermediate 58a (15 mg) in methanol (5 mL) and the mixture was refluxed for 2 h. The mixture was concentrated in vacuo to give the title compound (7 mg) as a white solid.

IR (nujol) 1654 (C-O) cm -1.

NMR (DMSO) δ (ppm) 9.17 (broad s, 1H); 8.88 (broad s, 1H); 7.93 (s, 1 H), 7.86 (s, 2 H); 7.23 (m, 1 H); 6.94 (m, 2H), 4.78 (t, 1H), 4.46 (dd, 1H); 3.88-3.83 (m, 2H); 3.79 (m, 1 H); 3.4 (m, 1 H); 3.28 (m, 1 H); 3.2 (d, 1 H); 3.06 (t, 1 HOUR); 2.84 (m, 1 H); 2.31 (m, 1 H), 2.27 (s, 3 H); 1.96 (m, 1 H); 1.74 (m, 1 H); 1.62 (m, 1 H).

MS: m / z = 504 [MH-HCl] +.

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Example 27

Hydrochloride [2- (3,5-bis-trifluoromethyl-phenyl) -pyrrolidin-1-yl] - [2- (S) - (4-fluoro-2-methyl-phenyl) -piperazin-1-yl] -methanone  (enantiomer B)

HCl conc. (0.3 mL) to a solution of intermediate 58b (20 mg) in methanol (5 mL) and the mixture was refluxed for 2 h. The mixture was concentrated in vacuo to give the title compound (11 mg) as a white solid.

IR (nujol) 1659 (C-O) cm -1.

NMR (DMSO) δ (ppm) 9.09 (broad m, 1H); 8.89 (broad m, 1H); 7.83 (s, 1 H), 7.52 (s, 2 H); 7.45 (dd, 1 H); 6.97 (td, 1H), 6.9 (dd, 1H); 4.93 (dd, 1H), 4.39 (dd, 1H); 3.88-3.22 (m, 6H); 3.07 (t, 1 H); 2.99 (m, 1 H); 2.3 (m, 1H), 2.25 (s, 3H); 1.80 (m, 1 H); 1.75 (m, 1 H); 1.63 (m, 1 H).

S: m / z = 504 [MH-HCl] +.

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Example 28

[2- (3,5-Bis-Trifluoromethyl-phenyl) -3,6-dihydro-2 H -pyridin-1-yl] - [2- (S) - (4-fluoro-2-methyl-phenyl) hydrochloride ) -piperazin-1-yl] -methanone (enantiomer A)

Trifluoroacetic acid (5 mL) was added to a solution of intermediate 62 (172 mg) in DCM (5 mL) and the resulting solution was stirred at rt for 30 minutes. The mixture was concentrated in vacuo , then divided between a solution of 10% potassium carbonate and AcOEt. The organic layer was dried and concentrated in vacuo : the residue was dissolved in Et2O and treated with 1M HCl in Et2O (5 mL) the mixture was stirred at rt for 30 min, then concentrated in vacuo and the residue was triturated with Et2O to give the title compound (90 mg) as a white solid.

IR (nujol) 1656 (C-O) cm -1.

NMR (DMSO) δ (ppm) 9.4-9.2 (broad s, 2H); 7.95 (s, 1 H); 7.54 (s, 2H); 7.32 (dd, 1 H); 6.98 (dd, 1H), 6.85 (dt, 1H); 5.9 (broad m, 1H); 5.72 (m, 1 H); 5.47 (d, 1 H); 4.57 (dd, 1 H); 4.41 (broad d, 1H); 3.4-3.25 (m, 5H); 3.14 (t, 1 H); 2.91 (t, 1 H); 2.72 (dd, 1H); 2.55 (m, 1 H), 2.37 (s, 3 H).

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Example 29

Hydrochloride [2- (3,5-bis-trifluoromethyl-phenyl) -piperidin-1-yl] - [2- (S) - (4-fluoro-2-methyl-phenyl) -piperazin-1-yl] -methanone (enantiomer A)

Palladium on carbon (10% -14 mg) was added to a solution of intermediate 62 (145 mg) in AcOEt (5 mL). The resulting mixture was stirred at 1 atm and rt under a hydrogen atmosphere for 3 hrs. The mixture was filtered and concentrated in vacuo . DCM (5 mL) and trifluoroacetic acid (5 mL) were added to the residue and the resulting solution was stirred at rt for 30 minutes. The mixture was concentrated in vacuo , then divided between a solution of 10% potassium carbonate and AcOEt. The organic layer was dried and concentrated in vacuo : the residue was dissolved in Et2O and treated with 1M HCl in Et2O (5 mL), the mixture was stirred at rt for 15 min, then it was concentrated in vacuo and the residue was triturated with Et2O to give the title compound (42 mg) as a white solid.

IR (nujol) 3200-2500 (NH2 +), 1656 (C-O) cm -1.

NMR (DMSO) δ (ppm) 9.4 (broad s, 2H); 7.92 (broad s, 1H); 7.48 (broad s, 2H); 7.43 (dd, 1 H); 6.97 (dd, 1H), 6.93 (m, 1H); 5.25 (broad m, 1H); 4.61 (dd, 1 H); 4.15 (broad d, 1 HOUR); 3.5-3.2 (broad m, 5H); 2.92 (t, 1 H); 2.79 (m, 1 HOUR); 2.36-2.42 (m, 4H); 1.78-1.58 (m, 4H); 1.17 (m, 1 H).

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Example 30

Hydrochloride [1- (3,5-bis-trifluoromethyl-phenyl) -but-3-enyl] -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid  (diastereoisomer A)

DCM (2 mL) and trifluoroacetic acid (5 mL) were added to intermediate 65 (44 mg) and the resulting solution was stirred at rt for 30 minutes. The mixture was concentrated in vacuo , then divided between a solution of 10% potassium carbonate and AcOEt. The organic layer was dried and concentrated in vacuo : the residue was dissolved in Et2O and treated with 1M HCl in Et2O (5 mL). The mixture was stirred at rt for 10 min, then concentrated in vacuo to give the title compound (43 mg) as a white solid.

NMR (DMSO) δ (ppm) 9.05 (broad s, 1H); 8.81 (broad s, 1H); 7.96 (broad s, 1H); 7.55 (broad s, 2H); 7.25 (dd, 1H); 6.97 (dd, 1H), 6.78 (dt, 1H); 5.7 (m, 1 H); 5.35 (dd, 1 H); 5.22-5.06 (2m, 2H), 4.47 (dd, 1H); 3.5-2.37 (m, 15H).

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Example 31

Hydrochloride [1- (3,5-bis-trifluoromethyl-phenyl) -but-3-enyl] -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid  (diastereoisomer B)

DCM (2 mL) and trifluoroacetic acid (5 mL) were added to intermediate 66 (44 mg) and the resulting solution was stirred at rt for 30 minutes. The mixture was concentrated in vacuo , then divided between a solution of 10% potassium carbonate and AcOEt. The organic layer was dried and concentrated in vacuo : the residue was dissolved in Et2O and treated with 1M HCl in Et2O (5 mL). The mixture was stirred at rt for 10 min, then concentrated in vacuo to give the title compound (39 mg) as a white solid.

IR (nujol): 3422 (NH2 +), 1726 (C-O) cm -1;

NMR (DMSO) δ (ppm) 9.24 (m wide, 1H); 9.02 (broad m, 1H); 7.99 (s, 1 H); 7.78 (s, 2H); 7.26 (dd, 1 H); 6.97 (dd, 1H), 6.87 (dt, 1H); 5.47 (m, 1 H); 5.2 (t, 1 H); 5.03 (dd, 1 H); 4.89 (d, 1 H); 4.49 (dd, 1 H); 3.36 (m, 2 H); 3.24 (m, 2 H); 2.97 (m, 2H); 2.85 (s, 3 H); 2.74 (t, 2H), 2.37 (s, 3H).

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Example 32

Hydrochloride [1- (3,5-bis-trifluoromethyl-phenyl) -2-methyl-propyl] -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid  (diastereoisomer A)

Trifluoroacetic acid (1 mL) was added to a solution of intermediate 77a (35 mg) in DCM (1.5 mL) and the resulting solution was stirred at rt for 30 minutes. The mixture was concentrated in vacuo , then divided between a solution of 10% potassium carbonate and AcOEt. The organic layer was dried and concentrated in vacuo : the residue was dissolved in Et2O and treated with 1M HCl in Et2O (1 mL). The mixture was stirred at rt for 10 min, then concentrated in vacuo and the residue was triturated with Et2O to give the title compound (20 mg) as a white solid.

NMR (d_ {6} -DMSO): δ (ppm) 8.87 (broad s, 2H); 8.02 (s, 1 H); 7.88 (s, 1 H); 7.26 (m, 1 H); 6.96 (m, 1 H); 6.86 (m, 1 H); 4.71 (broad m, 1H); 4.42 (dd, 1 H); 3.4-3.0 (m, 4H); 2.88-2.79 (m, 5H); 2.63-2.38 (m, 4H); 0.62 (d, 3H); 0.58 (d, 3 H).

MS: m / z = 520 [M-Cl] +.

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Example 33

Hydrochloride [1- (3,5-bis-trifluoromethyl-phenyl) -2-methyl-propyl] -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid  (diastereoisomer B)

Trifluoroacetic acid (1 mL) was added to a solution of intermediate 77b (37 mg) in DCM (1.5 mL) and the resulting solution was stirred at rt for 30 minutes. The mixture was concentrated in vacuo , then divided between a solution of 10% potassium carbonate and AcOEt. The organic layer was dried and concentrated in vacuo : the residue was dissolved in Et2O and treated with 1M HCl in Et2O (1 mL). The mixture was stirred at rt for 10 min, then concentrated in vacuo and the residue was triturated with Et2O to give the title compound (20 mg) as a white solid.

NMR (d_ {6} -DMSO): δ (ppm) 9.14-8.89 (broad s, 2H); 7.96 (s, 1 H); 7.69 (s, 2H); 7.02-6.95 (dd, 2H); 6.58 (m, 1 H); 4.71 (d, 1 HOUR); 4.45 (dd, 1 H); 3.5-3.2 (m, 4H); 2.95-2.80 (m, 5H); 2.6-2.38 (m, 4H); 0.87 (d, 3H); 0.72 (d, 3H).

MS: m / z = 520 [M-Cl] +.

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Example 3. 4

Hydrochloride [(3,5-bis-trifluoromethyl-phenyl) -cyclopropyl-methyl] -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid  (diastereoisomer A)

HCl conc. (50 µl) to a solution of intermediate 80 (10 mg) in methanol (1 mL) and the mixture was refluxed for 15 min. The mixture was concentrated in vacuo and the residue was triturated with Et 2} {O to give the title compound (4 mg) as a white solid.

NMR (DMSO) δ (ppm) 9.33 (m wide, 1H); 9.16 (m, 1 H); 8.0 (wide s, 1H), 7.79 (wide s, 2H); 7.3 (dd, 1 H); 6.95 (m, 2H), 4.48 (dd, 1H), 4.27 (d, 1H); 3.5-2.8 (m, 9H); 2.34 (s, 3H), 1.47 (m, 1H); 0.64 (m, 1 H); 0.45 (m, 1 H); 0.38 (m, 1 H); 0.08 (m, 1 H).

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Example 35

[2- (3,5-Bis-Trifluoromethyl-phenyl) -3,6-dihydro-2 H -pyridin-1-yl] - [2- (4-fluoro-2-methyl-phenyl) -piperazin- hydrochloride 1-yl] -methanone (diastereoisomer A)

Trifluoroacetic acid (5 mL) was added to a solution of intermediate 68 (172 mg) in DCM (5 mL) and the resulting solution was stirred at rt for 30 minutes. The mixture was concentrated in vacuo , then divided between a solution of 10% potassium carbonate and AcOEt. The organic layer was dried and concentrated in vacuo : the residue was dissolved in Et2O and treated with 1M HCl in Et2O (5 mL). The mixture was stirred at rt for 30 min, then concentrated in vacuo and the residue was triturated with Et2O to give the title compound (90 mg) as a white solid.

IR (nujol) 1656 (C-O) cm -1.

NMR (DMSO) δ (ppm) 9.23 (broad s, 1H); 9.17 (broad s, 2H); 7.89 (s, 1 H); 7.56 (s, 2H); 7.32 (dd, 1 H); 6.95 (dd, 1H), 6.82 (dt, 1H); 5.9 (m, 1 H); 5.72 (d, 1 H); 5.47 (d, 1 H); 4.6 (dd, 1 H); 4.4 (m, 1 H); 3.4-3.2 (m, 6H); 2.94 (m, 1 H); 2.7 (dd, 1 H); 2.56 (m, 1 H), 2.36 (s, 3 H).

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Example 36

Methane sulphonate [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-amide of acid 2- (S) - (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid

To a suspension of intermediate 81 (4.9 kg) in AcOEt (137.2 L) triethylamine (5.63 L) was added. The mixture was cooled to 0 ° C, then a solution of di-tert-butyl dicarbonate (3,134 kg) in AcOEt (24.5 l) over the course of 35 min, maintaining the temperature between 0 and 5 ° C. The suspension was stirred at 0 ° C for 15 min, at 20/25 ° C for 1 h, then washed with water (3 x 39.2 l), concentrated to leave 24.5 l and then added to a solution of triphosgene (1.97 kg) in AcOEt (24.5 l), cooled to 0 ° C. Was added then triethyl amine (3.28 l) over the course of 40 min, keeping the temperature between 0 and 8ºC. The suspension is stirred for 1 h and 45 min at 20/25 ° C and for 30 min at 70 ° C and then the solution of intermediate 9, diluted with AcOEt (49 l) and triethyl amine (2.6 L) was added over the course 30 min The mixture was refluxed for 15 h.

The reaction mixture, cooled to 20/25 ° C, was treated with a 10% aqueous solution of NaOH v / v (36.75 L). The organic phase was washed with 4% v / v HCl (46.55 l) and 11.5% w / w NaCl (4 x 24.5 l) then concentrated to leave 14.7 l and diluted with cyclohexane (39.2 l). The mixture was filtered through a silica pad (4.9 kg) which was washed twice with a mixture of CH and AcOEt 85/15 (2 x 49 L). To the eluted phases (14.7 l), cooled to 20/25 ° C, methyl tert-butyl ether (49 l) and methanesulfonic acid (4,067 l) were added. The mixture was washed with 10% NaOH v / v (31.85 L) and then with water (4 x 31.85 L). The organic phase was concentrated to leave 9.8 l, methyl tert-butyl ether (49 l) was added and the solution was filtered through a 5 micrometer filter and then concentrated to leave 9.8 l. At 20/25 ° C MTBE (29.4 L) and methanesulfonic acid (1.098 L) were added. The suspension was refluxed for 10 min, stirred at 20/25 ° C for 10 h and for 2 h at 0 ° C. Then, the precipitated material was filtered, washed with methyl-tert-butyl ether (4.9 L), dried under vacuum at 20/25 ° C for 24 h to obtain the title compound (5,519 kg) as a material solid white.

1 H-NMR (DMSO): δ (ppm) 8.99 (broad m, 1H); 8.66 (broad m, 1H); 8.00 (broad s, 1H); 7.69 (broad s, 2H); 7.27 (dd, 1 H); 7.00 (dd, 1 H); 6.83 (m, 1 H); 5.32 (q, 1 H); 4.47 (dd, 1 H); 3.50-3.20 (m, 4H); 2.96 (m, 2H); 2.72 (s, 3 H); 2.37 (s, 3 H); 2.28 (s, 3 H); 1.46 (d, 3H).

ES <+> ( m / z ): 492 [MH-CH 3 SO 3 H] +

ES <-> ( m / z ): 586 [MH] -; 95 [CH 3 SO 3] -

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Example 37

[1- (R) - (3,5-Bis-trifluoromethyl-phenyl) -ethyl] -methyl-amide of acid 2- (S) - (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid

To a solution of intermediate 40a (15.6 g) in anhydrous THF (94 ml), at 0 ° C, under N 2, 1 M BH 3 / THF (154 ml) was added. The solution was heated at reflux for 3 h. 37% HCl (54 ml) was added slowly keeping the reaction mixture in an ice bath, and the reaction mixture was stirred at rt for 1 h. Water (125 ml) was then added and solid NaHCO3 (62.4 g) was added portionwise until a pH of 6.5 was reached. The aqueous phase was extracted with Et2O (4 x 160 ml) and the combined organic extracts were dried over Na2SO4, the solid materials were filtered and evaporated to leave a colorless oil, which was purified by flash chromatography (on silica gel, with a mixture of EtOAc and methanol 7/3). The product obtained was suspended in Et2O (220 ml) and washed with saturated NaHCO3 (2 x 36 ml). The combined organic phases were dried (over Na2SO4) and evaporated to give the title compound as a white foam (8.7 g).

1 H-NMR (CDCl 3) δ (ppm) 7.78 (s, 1 H); 7.60 (s, 2 H); 7.28 (m, 1 H); 6.85 (dd, 1 HOUR); 6.79 (td, 1 H); 5.53 (q, 1 H); 4.43 (dd, 1 H); 2.9-3.5 (m, 5H); 2.78 (m, 1 H); 2.71 (s, 3 H); 2.43 (s, 3H); 1.47 (d, 3 H).

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Example 38

Hydrochloride [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-amide of acid 2- (S) - (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid

The compound of Example 37 (0.1 g) was dissolved in diethyl ether (0.8 ml) at room temperature, then a 1 M solution of HCl in diethyl ether (0.6 ml) was added. The suspension was stirred at 3 ° C for 3 hours, then filtered and washed with diethyl ether (1 ml) to give the title compound (0.015 g) as a white solid material.

1 H-NMR (DMSO) δ (ppm) 9.31 (broad m, 1H); 9.11 (broad m, 1H); 8.02 (broad s, 1H); 7.72 (broad s, 2H); 7.28 (dd, 1 H); 7.00 (dd, 1 H); 6.84 (m, 1 H); 5.34 (q, 1 H); 4.54 (dd, 1 H); 3.50-3.20 (m, 4H); 3.08 (m, 1 H); 2.93 (m, 1 H); 2.73 (s, 3 H); 2.28 (s, 3 H); 1.48 (d, 3H).

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Pharmaceutical Examples A. Capsules / tablets

17

The active ingredient is mixed with the others excipients The mixture can be used to refill capsules of jelly or can be compressed to form tablets using punches appropriate. The tablets can be coated using techniques and conventional coatings.

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B. Tablets

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The active ingredient is mixed with lactose, microcrystalline cellulose and a part of croscarmellose sodium. The mixture is granulated with povidone after dispersing it in an appropriate solvent (ie water). The granule, after having dried and shredded, mixed with the remnants excipients The mixture can be compressed using punches appropriate and in the tablets can be coated using techniques and conventional coatings.

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C. Bowling

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The formulation can be packaged in blisters or vials and glass syringes with a rubber stopper and a seal plastic and metal upper (for vials only).

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D. Infusion

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The formulation can be packaged in vials of glass or in a plastic bag.

The affinity of the compound of the invention for the NK1 receptor was determined using the NK1 receptor binding affinity method by measuring in vitro the ability of the compounds to displace the [3H] -substance P (SP) from of recombinant human NK1 receptors, expressed in Chinese hamster ovary (CHO) cell membranes. Affinity values are expressed as the negative logarithm of the inhibition constant (Ki) of displacing ligands (pKi).

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The pKi values obtained as the average of at least two determinations with representative compounds of invention, are given in the following table:

twenty-one

The capacity of the compounds of formula (I) next to the NK_1 receptor can be determined using the model of gerbil leg paracentesis as described by Rupniak & Williams, in Eur. Jour. from Pharmacol., 1994.

The compound was administered orally and a an agonist agent of NK1 was infused an hour later (e.g. delta-aminovaleryl 6 [Pro 9, Me-Leu 10] - substance P (7-11)) (3 pmol in 5 µl of icv) directly in the cerebral ventricles of animals. The duration of the rear leg paracentesis induced by the agonist agent of NK1 (eg delta-aminovaleryl 6 [Pro 9, Me-Leu 10] - substance P (7-11)) was recorded continuously for 3 Min using a stopwatch. The dose of the test compound, required to inhibit paracentesis induced by 50% agonist agent of NK1 (e.g. delta-aminovaleryl 6 [Pro 9, Me-Leu 10] - substance P (7-11)) expressed as mg / kg, it was cited as ID50 values. Alternatively, the compounds can be administer subcutaneously or intraperitoneally.

The representative results obtained for the compounds of formula (I) when given by oral administration they are presented in the following table

2. 3

No adverse effects have been observed when compounds of formula (I) have been administered to gerbil in active pharmacological doses.

Claims (12)

1. A composition comprising a compound of formula (I) 24 at that R represents a halogen atom or a group C 1-4 alkyl; R1 represents hydrogen or an alkyl group C 1-4; R2 represents hydrogen, an alkyl group C 1-4, or an alkenyl group C 2-6 or C 3-7 cycloalkyl; or R1 and R2 together with the nitrogen and carbon atom to which are united respectively represent a heterocyclic group of 5 to 6 members; R 3 represents a trifluoromethyl group, a C 1-4 alkyl, an alkoxy C 1-4, a trifluoromethoxy or a halogen; R 4 represents hydrogen, a group (CH2) qR7 {or (CH 2) rCO (CH 2) pR 7; R 5 represents hydrogen or an alkyl group C 1-4 or a COR 6; R 7 represents hydrogen, hydroxy or NR_ {8} R_ {9} in which R_ {8} and R_ {9} represent independently hydrogen or C 1-4 alkyl optionally substituted by hydroxy or by amino; R 10 represents hydrogen, an alkyl group C_ {1-4} or R_ {10} together with R2 represents a group C 3-7 cycloalkyl; m is zero or an integer from 1 to 3; n is zero or an integer of 1 of 3; both p and r are independently zero or an integer from 1 to 4; q is an integer from 1 to 4; to condition that when R_ {1} and R2 together with the atom of nitrogen and carbon to which they are attached respectively represent a 5- to 6-membered heterocyclic group, i) m being 1 or 2; ii) when m is 1, R is not fluorine and iii) when m is 2, the two R substituents are not fluorine, or their salts or solvates pharmaceutically acceptable and a selective inhibitor of serotonin reuptake. 2. A compound according to claim 1, wherein the compound of formula (I) is selected from from: (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid; (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (2-Isopropyl-phenyl) -piperazin-1-carboxylic acid; (3,5-bis-trifluoromethyl-benzyl) methyl amide of the acid 2- (4-Fluoro-3-methyl-phenyl) -piperazin-1-carboxylic acid; (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (2,4-Difluoro-phenyl) -piperazin-1-carboxylic acid; [1- (3,5-bis-trifluoromethyl-phenyl) ethyl] -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid; (3,4-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (4-fluoro-phenyl) -piperazin-1-carboxylic acid; (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2-phenyl-piperazin-1-carboxylic; (3,5-Bistrifluoromethyl-benzyl) -methyl-amide of the acid 2- (2,4-dichloro-phenyl) -piperazin-1-carboxylic acid; (3,5-Bistrifluoromethyl-benzyl) -methyl-amide of the acid 2- (3,4-dichloro-phenyl) -piperazin-1-carboxylic acid; (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -3-methyl-piperazin-1-carboxylic acid; (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (2-methyl-4-fluoro-phenyl) -6-methyl-piperazin-1-carboxylic acid; [1- (3,5-bis-trifluoromethyl-phenyl) ethyl] -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid; (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 4- (2-amino-acetyl) -2- (S) - (4-fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid; (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (S) - (4-Fluoro-2-methyl-phenyl) -4- (piperidin-4-carbonyl) -piperazin-1-carboxylic acid; (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 4- (2-amino-ethyl) -2- (S) - (4-fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid; [(1-3,5-bis-trifluoromethyl-phenyl) -cyclopropyl] -methyl-amide of the acid 2- (S) - (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid; [2- (3,5-bis-trifluoromethyl-phenyl) -pyrrolidin-1-yl] - [2- (S) - (4-fluoro-2-methyl-phenyl) -piperazin-1-yl] -methanone; [2- (3,5-bis-trifluoromethyl-phenyl) -3,6-dihydro-2H-pyridin-1-yl] - [2- (S) - (4-fluoro-2-methyl-phenyl) -piperazin -1-il] -meta-
ninth; [2- (3,5-bis-trifluoromethyl-phenyl) -piperidin-1-yl] - [2- (S) - (4-fluoro-2-methyl-phenyl) -piperazin-1-yl] -methanone; [1- (3,5-bis-trifluoromethyl-phenyl) -but-3-enyl] -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid; [1- (3,5-bis-trifluoromethyl-phenyl) -2-methyl-propyl] -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid; [(3,5-bis-trifluoromethyl-phenyl) -cyclopropyl-methyl] -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid; or its enantiomers or pharmaceutically salts acceptable (eg, hydrochloride, methanesulfonate, acetate) and Solvates 3. A compound as claimed in the claim 1 or 2, wherein the compound of formula (I) is [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-amide  of the acid 2- (S) - (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid or its hydrochloride, methanesulfonate or acetate. 4. A compound according to any of the claims 1 to 3, wherein the compound of formula (I) is methanesulfonate [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-amide of the acid 2- (S) - (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid. 5. A composition according to the claim 1, wherein the selective reuptake inhibitor  of serotonin is selected from fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline and zimeldina. 6. A composition according to any of claims 1 to 5 for use in the treatment and / or the prophylaxis of depression and / or anxiety. 7. A pharmaceutical formulation comprising a composition according to any one of claims 1 to 5 in admixture with one or more physiologically active vehicles or excipients acceptable. 8. The use of a compound of formula (I) and a serotonin reuptake inhibitor in the manufacture of a medication for simultaneous or sequential administration for treatment and / or prophylaxis of depression and / or anxiety. 9. The use according to claim 8, in wherein the compound of formula (I) is selected from: (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid; (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (2-Isopropyl-phenyl) -piperazin-1-carboxylic acid; (3,5-bis-trifluoromethyl-benzyl) methyl amide of the acid 2- (4-Fluoro-3-methyl-phenyl) -piperazin-1-carboxylic acid; (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (2,4-Difluoro-phenyl) -piperazin-1-carboxylic acid; [1- (3,5-bis-trifluoromethyl-phenyl) ethyl] -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid; (3,4-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (4-fluoro-phenyl) -piperazin-1-carboxylic acid; (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2-phenyl-piperazin-1-carboxylic; (3,5-Bistrifluoromethyl-benzyl) -methyl-amide of the acid 2- (2,4-dichloro-phenyl) -piperazin-1-carboxylic acid; (3,5-Bistrifluoromethyl-benzyl) -methyl-amide of the acid 2- (3,4-dichloro-phenyl) -piperazin-1-carboxylic acid; (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -3-methyl-piperazin-1-carboxylic acid; (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (2-methyl-4-fluoro-phenyl) -6-methyl-piperazin-1-carboxylic acid; [1- (3,5-bis-trifluoromethyl-phenyl) ethyl] -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid; (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 4- (2-amino-acetyl) -2- (S) - (4-fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid; (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 2- (S) - (4-Fluoro-2-methyl-phenyl) -4- (piperidin-4-carbonyl) -piperazin-1-carboxylic acid; (3,5-bis-trifluoromethyl-benzyl) -methyl-amide of the acid 4- (2-amino-ethyl) -2- (S) - (4-fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid; [(1-3,5-bis-trifluoromethyl-phenyl) -cyclopropyl] -methyl-amide of the acid 2- (S) - (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid; [2- (3,5-bis-trifluoromethyl-phenyl) -pyrrolidin-1-yl] - [2- (S) - (4-fluoro-2-methyl-phenyl) -piperazin-1-yl] -methanone; [2- (3,5-bis-trifluoromethyl-phenyl) -3,6-dihydro-2H-pyridin-1-yl] - [2- (S) - (4-fluoro-2-methyl-phenyl) -piperazin -1-il] -meta-
ninth; [2- (3,5-bis-trifluoromethyl-phenyl) -piperidin-1-yl] - [2- (S) - (4-fluoro-2-methyl-phenyl) -piperazin-1-yl] -methanone; [1- (3,5-bis-trifluoromethyl-phenyl) -but-3-enyl] -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid; [1- (3,5-bis-trifluoromethyl-phenyl) -2-methyl-propyl] -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid; [(3,5-bis-trifluoromethyl-phenyl) -cyclopropyl-methyl] -methyl-amide of the acid 2- (4-Fluoro-2-methyl-phenyl) -piperazin-1-carboxylic acid; or its enantiomers or pharmaceutically salts acceptable (for example, hydrochloride, methanesulfonate, acetate) or Solvates 10. The use according to claim 8 or 9, wherein the compound of formula (I) is [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-amide  of the acid 2- (S) - (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid or its hydrochloride, methanesulfonate or acetate. 11. Use in accordance with any of the claims 8 to 10, wherein the compound of formula (I) is select from methanesulfonate from [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-amide of the acid 2- (S) - (4-Fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid. 12. The use according to claim 8, in which the selective serotonin reuptake inhibitor is select from fluoxetine, citalopram, femoxetine, Fluvoxamine, paroxetine, indalpine, sertraline or zimeldine.